Socioeconomic Inequalities in Childhood Vaccination in India: Pathways and Interventions

India has the largest number of children aged under 5 years of any country in the world but also one of the lowest childhood immunization rates globally. Important health initiatives of the Indian government such as the Universal Immunization Program and the Reproductive and Child Health program have increased childhood vaccination rates and decreased socioeconomic inequalities. However, there is a paucity of national level studies that have utilized data collected after 2006 to examine these issues. In this dissertation, we examined time-trends in socioeconomic inequalities in childhood vaccination over an 11-year period between 2002 and 2013 using cross-sectional data collected during three distinct time-periods: 2002-2004, 2007-2008 and 2012-2013 in 29 Indian states. We assessed the role of availability and acceptability of health services as potential mediators in the association between socioeconomic status and childhood vaccination in 20 Indian states during 2007-2008 and 2012-2013. Finally, we examined the cost-effectiveness of the accredited social health activist (ASHA) program, a community health worker initiative introduced under National Rural Health Mission in 2005, in improving measles vaccination. We examined the associations between socioeconomic status (SES) and full childhood vaccination for three time-periods, stratifying our analyses by time-period and empowered action group (EAG) state status. Non-EAG states experienced decreased full vaccination rates in 2012-2013 compared to 2007-2008. We found that while SES based-inequalities in vaccination rate decreased in both EAG and non-EAG states, they were present to a greater degree in EAG states for all three time-periods; however, the gap in SES based-disparities between EAG and non-EAG states decreased during this 11-year time-period. To examine these inequalities further, we conducted mediation analyses to explore how availability and accessibility of vaccination services could mediate the association between SES and full childhood vaccination during 2007-2008 and 2012-2013. In our analyses, the indirect effect mediated by availability and acceptability of health services was positive and the direct effect of SES on full childhood vaccination was negative for both time-periods. The total direct effect of SES on full childhood was positive in 2007-2008 while negative in 2012-2013. Finally, we conducted a cost-effectiveness analysis of ASHAs with regards to childhood measles vaccination, obtaining parameter estimates for our cohort simulation model from 2012-2013 data and prior literature. ASHAs were highly cost-effective in our univariate sensitivity analyses and most of the bivariate and probabilistic sensitivity analyses. ASHAs remained cost-effective even when their financial incentive to perform measles vaccination related services was increased by 10 times. They remained cost-effective in long-term scenarios where the cohort size of a village decreased over time as more and more children were vaccinated. In view of these findings, the Indian government may want to focus its efforts on both EAG and non-EAG states to receive adequate funding and resources to ensure gains in vaccination are not lost. This study also demonstrates the possibility of vaccine hesitancy and lower full vaccination rates among children from richer households due to availing of vaccine services from private healthcare providers who tend to be less accountable than public healthcare providers in ensuring full vaccination of children. Finally, we quantitatively demonstrate the cost-effectiveness of ASHAs even when considering a single outcome among their myriad responsibilities and show that the financial compensation for ASHAs for services they render can be increased without compromising their cost-effectiveness.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145903/1/bdeepti_1.pd

Critical roles of arginine in growth and biofilm development by Streptococcus gordonii

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112199/1/mmi13023.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/112199/2/mmi13023-sup-0001-si.pd

L-Arginine Destabilizes Oral Multi-Species Biofilm Communities Developed in Human Saliva

<div><p>The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS) in pooled filter-sterilized cell-free saliva (CFS) at 37^oC. The addition of pH neutral L-arginine monohydrochloride (LAHCl) to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm³/μm²) developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of <i>Streptococcus</i> and <i>Veillonella</i> species increased and the proportion of Gram-negative bacteria such as <i>Neisseria</i> and <i>Aggregatibacter</i> species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC), an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl moderates multi-species oral biofilm development and community composition and enhances the activity of CPC. The incorporation of LAHCl into oral healthcare products may be useful for enhanced biofilm control.</p></div

Differences in architecture of oral biofilms grown a static biofilm system containing different concentrations of L-arginine monohydrochloride (LAHCl).

<p>Images show representative 3D renderings of 22 h-old oral biofilms grown from a cell-containing saliva (CCS) inoculum in the static biofilm system containing cell free saliva (CFS) supplemented with different concentrations of LAHCl. Green signal (Syto 9) indicates viable cells and red signal (propidium iodide) indicates damaged/dead cells. Upper renderings (A₁–F₁) are of the x–y plane. Middle renderings (A₂–F₂) are of the x–z plane. Lower renderings (A₃–F₃) represent an angled view (x–y–z). Bars represent 50 μm. The associated table shows changes in percentage of cell viability with means presented in bold and standard deviations shown in parentheses (each derived from at least 27 images from nine biological replicates). *P<0.05; **P<0.01: significant differences from the CFS control.</p

Effects of flowing saliva supplemented with different LAHCl concentrations on the development of oral biofilms for 20 h in the Bioflux system.

<p>The graph shows differences in biofilm biovolume and representative CLSM 3D renderings are included to highlight differences in biofilm architecture. Light blue colored star symbols embedded in the graph indicate a significant increase in average biofilm biovolume over CFS control and orange colored star symbols embedded in the graph indicate a significant decrease in average biofilm biovolume over CFS control. For the rendered biofilms within the embedded images, green colored cells indicate viable cells and red colored cells indicate damaged/dead cells. Bars represent 20 μm. The associated table shows, in addition to the biovolumes highlighted in the graph, changes in average biofilm thickness, average biofilm roughness, and cell viability. For data presented in the associated table, means are shown in bold and standard deviations are shown in parentheses (each derived from at least 18 images from six biological replicates). *P<0.05; **P<0.01; ***P<0.001: significant differences from the CFS control.</p

LAHCl affects preformed biofilms and enhances antimicrobial effectiveness.

<p>Demonstration that a 60 s exposure of oral multi-species biofilms developed in flowing cell free saliva (CFS) to solutions supplemented with LAHCl reduces biofilm biovolume and enhances antimicrobial efficacy of cetylpyridinium chloride (CPC). Representative biofilm renderings show 20 h oral biofilms developed from pooled CCS in flowing CFS in the Bioflux microfluidic system and subsequently exposed for 60 s to 0.05% or 0.01% CPC with or without 500 mM LAHCl. Green signal (Syto 9) shows viable cells, red signal (propidium iodide) shows damaged/dead cells. Upper images (A₁–F₁) are of the x–y plane. Middle images (A₂–F₂) are of the x–z plane. Lower images (A₃–F₃) are an angled view of each plane (x–y–z). Bars represent 20 μm. Associated table shows changes in cell viability, biofilm biovolume, thickness, and roughness. For data presented in the associated table, means are presented in bold and standard deviations are shown in parentheses (each derived from at least 9 images from three biological replicates). *P<0.05, **P<0.01: significant differences from the H₂O control; ▪P<0.05, ▪▪P<0.01: significant differences from 0.05% CPC treatment; †P<0.05, ††P<0.01: significant differences from 0.01% CPC treatment.</p

Sustained exposure to LAHCl alters biofilm community composition.

<p>Oral biofilms developed in the Bioflux system containing flowing CFS supplemented with 500 mM LAHCl display an altered biofilm community composition compared to those developed in non-supplemented CFS. Data derived from bacterial tag-encoded FLX amplicon pyrosequencing of oral biofilms grown for 20 h in three Bioflux microfluidic channels exposed to flowing CFS (control) and three Bioflux microfluidic channels exposed to flowing CFS supplemented with 500 mM LAHCl. (<b>A</b>) Comparison of OTU (97% identity) richness derived from rarefaction curves for biofilms developed in non-supplemented CFS (black square symbols) and biofilms developed in CFS supplemented with 500 mM LAHCl (grey square symbols). (<b>B</b>) Comparison of differences in abundance of phyla. Black bars represent data derived from the analysis of biofilms developed in flowing non-supplemented CFS while the grey bars represent data derived from the analysis of biofilms developed in CFS supplemented with 500 mM LAHCl. (<b>C</b>) Comparisons of differences in abundances of genera whereby abundances are normalized to biofilm biovolume (calculated from data presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121835#pone.0121835.g002" target="_blank">Fig 2</a>). Note color coding (from left to right in the key) follows the order from most abundant in the CFS control. Far right color-coded bar is a magnified view of the community composition of the biofilm developed in CFS supplemented with 500 mM LAHCl. Supporting data is available in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121835#pone.0121835.s004" target="_blank">S1 Table</a>.</p

A model showing the proposed biofilm destabilizing effects of short-term exposure (transient; minutes) and longer-term exposure (sustained; hours) to high millimolar (≥100mM) LAHCl concentrations in flowing saliva.

<p>The model shows the effect of LAHCl on a well-developed multi-species biofilm (with respect to architecture and species composition) although similar destabilizing effects would occur on multi-species biofilms of younger or older developmental age. Cell shapes and sizes are not to scale. Postulated effects are based on data presented in this manuscript and on previous observations of the effects of L-arginine on bacterial cells and cell-cell interactions, as discussed in the body of the text.</p

Global, regional and national burden of rheumatoid arthritis 1990-2017: A systematic analysis of the Global Burden of Disease study 2017

Objectives: To provide the level and trends of prevalence, incidence and disability adjusted life years (DALYs) for rheumatoid arthritis (RA) in 195 countries from 1990 to 2017 by age, sex, Socio-demographic Index (SDI; a composite of sociodemographic factors) and Healthcare Access and Quality (an indicator of health system performance) Index. Methods: Data from the Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2017 were used. GBD 2017 modelled the burden of RA for 195 countries from 1990 to 2017, through a systematic analysis of mortality and morbidity data to estimate prevalence, incidence and DALYs. All estimates were presented as counts and age-standardised rates per 100 000 population, with uncertainty intervals (UIs). Results: Globally, the age-standardised point prevalence and annual incidence rates of RA were 246.6 (95% UI 222.4 to 270.8) and 14.9 (95% UI 13.3 to 16.4) in 2017, which increased by 7.4% (95% UI 5.3 to 9.4) and 8.2% (95% UI 5.9 to 10.5) from 1990, respectively. However, the age-standardised rate of RA DALYs per 100 000 population was 43.3 (95% UI 33.0 to 54.5) in 2017, which was a 3.6% (95% UI -9.7 to 0.3) decrease from the 1990 rate. The age-standardised prevalence and DALY rates increased with age and were higher in females; the rates peaked at 70-74 and 75-79 age groups for females and males, respectively. A non-linear association was found between age-standardised DALY rate and SDI. The global age-standardised DALY rate decreased from 1990 to 2012 but then increased and reached higher than expected levels in the following 5 years to 2017. The UK had the highest age-standardised prevalence rate (471.8 (95% UI 428.9 to 514.9)) and age-standardised incidence rate (27.5 (95% UI 24.7 to 30.0)) in 2017. Canada, Paraguay and Guatemala showed the largest increases in age-standardised prevalence rates (54.7% (95% UI 49.2 to 59.7), 41.8% (95% UI 35.0 to 48.6) and 37.0% (95% UI 30.9 to 43.9), respectively) and age-standardised incidence rates (48.2% (95% UI 41.5 to 55.1), 43.6% (95% UI 36.6 to 50.7) and 36.8% (95% UI 30.4 to 44.3), respectively) between 1990 and 2017. Conclusions: RA is a major global public health challenge. The age-standardised prevalence and incidence rates are increasing, especially in countries such as Canada, Paraguay and Guatemala. Early identification and treatment of RA is vital especially among females, in order to reduce the ongoing burden of this condition. The quality of health data needs to be improved for better monitoring of disease burden

Global, regional, and national burden of neck pain in the general population, 1990-2017:systematic analysis of the Global Burden of Disease Study 2017

Objective To use data from the Global Burden of Disease Study between 1990 and 2017 to report the rates and trends of point prevalence, annual incidence, and years lived with disability for neck pain in the general population of 195 countries. Design Systematic analysis. Data source Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Main outcome measures Numbers and age standardised rates per 100 000 population of neck pain point prevalence, annual incidence, and years lived with disability were compared across regions and countries by age, sex, and sociodemographic index. Estimates were reported with uncertainty intervals. Results Globally in 2017 the age standardised rates for point prevalence of neck pain per 100 000 population was 3551.1 (95% uncertainty interval 3139.5 to 3977.9), for incidence of neck pain per 100 000 population was 806.6 (713.7 to 912.5), and for years lived with disability from neck pain per 100 000 population was 352.0 (245.6 to 493.3). These estimates did not change significantly between 1990 and 2017. The global point prevalence of neck pain in 2017 was higher in females compared with males, although this was not significant at the 0.05 level. Prevalence increased with age up to 70-74 years and then decreased. Norway (6151.2 (95% uncertainty interval 5382.3 to 6959.8)), Finland (5750.3 (5058.4 to 6518.3)), and Denmark (5316 (4674 to 6030.1)) had the three highest age standardised point prevalence estimates in 2017. The largest increases in age standardised point prevalence estimates from 1990 to 2017 were in the United Kingdom (14.6% (10.6% to 18.8%)), Sweden (10.4% (6.0% to 15.4%)), and Kuwait (2.6% (2.0% to 3.2%)). In general, positive associations, but with fluctuations, were found between age standardised years lived with disability for neck pain and sociodemographic index at the global level and for all Global Burden of Disease regions, suggesting the burden is higher at higher sociodemographic indices. Conclusions Neck pain is a serious public health problem in the general population, with the highest burden in Norway, Finland, and Denmark. Increasing population awareness about risk factors and preventive strategies for neck pain is warranted to reduce the future burden of this condition