Summary Increasing demand for better quality data and more investment to strengthen civil registration and vital statistics (CRVS) systems will require increased emphasis on objective, comparable, ...cost-effective monitoring and assessment methods to measure progress. We apply a composite index (the vital statistics performance index VSPI) to assess the performance of CRVS systems in 148 countries or territories during 1980–2012 and classify them into five distinct performance categories, ranging from rudimentary (with scores close to zero) to satisfactory (with scores close to one), with a mean VSPI score since 2005 of 0·61 (SD 0·31). As expected, the best performing systems were mostly in the European region, the Americas, and Australasia, with only two countries from east Asia and Latin America. Most low-scoring countries were in the African or Asian regions. Globally, only modest progress has been made since 2000, with the percentage of deaths registered increasing from 36% to 38%, and the percentage of children aged under 5 years whose birth has been registered increasing from 58% to 65%. However, several individual countries have made substantial improvements to their CRVS systems in the past 30 years by capturing more deaths and improving accuracy of cause-of-death information. Future monitoring of the effects of CRVS strengthening will greatly benefit from application of a metric like the VSPI, which is objective, costless to compute, and able to identify components of the system that make the largest contributions to good or poor performance.
Summary Background With 4 years until 2015, it is essential to monitor progress towards Millennium Development Goals (MDGs) 4 and 5. Although estimates of maternal and child mortality were published ...in 2010, an update of estimates is timely in view of additional data sources that have become available and new methods developed. Our aim was to update previous estimates of maternal and child mortality using better data and more robust methods to provide the best available evidence for tracking progress on MDGs 4 and 5. Methods We update the analyses of the progress towards MDGs 4 and 5 from 2010 with additional surveys, censuses, vital registration, and verbal autopsy data. For children, we estimate early neonatal (0–6 days), late neonatal (7–28 days), postneonatal (29–364 days), childhood (ages 1–4 years), and under-5 mortality. We use an improved model for estimating mortality by age under 5 years. For maternal mortality, our updated analysis includes greater than 1000 additional site-years of data. We tested a large set of alternative models for maternal mortality; we used an ensemble model based on the models with the best out-of-sample predictive validity to generate new estimates from 1990 to 2011. Findings Under-5 deaths have continued to decline, reaching 7·2 million in 2011 of which 2·2 million were early neonatal, 0·7 million late neonatal, 2·1 million postneonatal, and 2·2 million during childhood (ages 1–4 years). Comparing rates of decline from 1990 to 2000 with 2000 to 2011 shows that 106 countries have accelerated declines in the child mortality rate in the past decade. Maternal mortality has also continued to decline from 409 100 (uncertainty interval 382 900–437 900) in 1990 to 273 500 (256 300–291 700) deaths in 2011. We estimate that 56 100 maternal deaths in 2011 were HIV-related deaths during pregnancy. Based on recent trends in developing countries, 31 countries will achieve MDG 4, 13 countries MDG 5, and nine countries will achieve both. Interpretation Even though progress on reducing maternal and child mortality in most countries is accelerating, most developing countries will take many years past 2015 to achieve the targets of the MDGs 4 and 5. Similarly, although there continues to be progress on maternal mortality the pace is slow, without any overall evidence of acceleration. Immediate concerted action is needed for a large number of countries to achieve MDG 4 and MDG 5. Funding Bill & Melinda Gates Foundation.
Summary In this Series paper, we examine whether well functioning civil registration and vital statistics (CRVS) systems are associated with improved population health outcomes. We present a ...conceptual model connecting CRVS to wellbeing, and describe an ecological association between CRVS and health outcomes. The conceptual model posits that the legal identity that civil registration provides to individuals is key to access entitlements and services. Vital statistics produced by CRVS systems provide essential information for public health policy and prevention. These outcomes benefit individuals and societies, including improved health. We use marginal linear models and lag-lead analysis to measure ecological associations between a composite metric of CRVS performance and three health outcomes. Results are consistent with the conceptual model: improved CRVS performance coincides with improved health outcomes worldwide in a temporally consistent manner. Investment to strengthen CRVS systems is not only an important goal for individuals and societies, but also a development imperative that is good for health.
Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) colonize the gut mucosa via attaching and effacing (A/E) lesions. For years cultured cells were used as model systems to study ...A/E lesion formation, which showed actin accumulation under attached bacteria that can be raised above the plasma membrane in a pedestal-shaped structure. Studies of prototypical strains revealed that although both converge on N-WASP EPEC and EHEC O157:H7 use different actin polymerization pathways. While EPEC use the Tir-Nck pathway, TirEHECO₁₅₇ cooperates with TccP/EspFU to activate N-WASP. However, recent in vitro studies revealed a common EPEC and EHEC Tir-dependent and Nck-independent inefficient actin polymerization pathway. Unexpectedly, bacterial populations studies demonstrated that most non-O157 EHEC strains and EPEC lineage 2 strains can utilize both the Nck and TccP2 pathways in vitro. Importantly, in vivo and ex vivo mucosal infections have shown efficient A/E lesion formation independently of Nck and TccP. This review covers the progression in our understanding of EPEC and EHEC infection, through the different milestones obtained using cultured cells, to the realization that EPEC and EHEC have much more in common than previously appreciated and that mucosal attachment and microvillous effacement may be the key events, rather than pedestal formation.
Curli are adhesive fimbriae of Escherichia coli and Salmonella enterica. Expression of curli (csgA) and cellulose (bcsA) is co-activated by the transcriptional activator CsgD. In this study, we ...investigated the contribution of curli and cellulose to the adhesive properties of enterohaemorragic (EHEC) O157:H7 and enteropathogenic E. coli (EPEC) O127:H6. While single mutations in csgA, csgD or bcsA in EPEC and EHEC had no dramatic effect on cell adherence, double csgAbcsA mutants were significantly less adherent than the single mutants or wild-type strains to human colonic HT-29 epithelial cells or to cow colon tissue in vitro. Overexpression of csgD (carried on plasmid pCP994) in a csgD mutant, but not in the single csgA or bscA mutants, led to significant increase in adherence and biofilm formation in EPEC and EHEC, suggesting that synchronized over-production of curli and cellulose enhances bacterial adherence. In line with this finding, csgD transcription was activated significantly in the presence of cultured epithelial cells as compared with growth in tissue culture medium. Analysis of the influence of virulence and global regulators in the production of curli in EPEC identified Fis (factor for inversion stimulation) as a, heretofore unrecognized, negative transcriptional regulator of csgA expression. An EPEC E2348/69Δfis produced abundant amounts of curli whereas a double fis/csgD mutant yielded no detectable curli production. Our data suggest that curli and cellulose act in concert to favour host colonization, biofilm formation and survival in different environments.
Advances in the understanding of the pathogenesis of enterohaemorrhagic Escherichia coli (EHEC) have greatly benefited from the use of human epithelial cell lines under aerobic conditions. However, ...in the target site of EHEC infection, the human intestine, conditions are microaerobic. In our study we used polarized human colon carcinoma cells in a vertical diffusion chamber system to investigate the influence of reduced apical oxygen levels on EHEC colonization. While apical microaerobiosis did not affect cell integrity and barrier function, numbers of adherent bacteria were significantly increased under low compared with high apical oxygen concentrations. In addition, expression and translocation of EHEC type III secreted (T3S) effector proteins was considerably enhanced under microaerobic conditions and dependent on the presence of host cells. Increased colonization was mainly mediated via EspA as adherence levels of an isogenic deletion mutant were not influenced by low oxygen levels. Other potential adherence factors (E. coli common pilus and flagella) were only minimally expressed under high and low oxygen levels. Addition of nitrate and trimethylamine N-oxide as terminal electron acceptors for anaerobic respiration failed to further increase bacterial colonization or T3S under microaerobiosis. This study indicates that EHEC T3S and colonization are enhanced by the microaerobic environment in the gut and therefore might be underestimated in conventional aerobic cell culture systems.
Abstract
Penguins lost the ability to fly more than 60 million years ago, subsequently evolving a hyper-specialized marine body plan. Within the framework of a genome-scale, fossil-inclusive ...phylogeny, we identify key geological events that shaped penguin diversification and genomic signatures consistent with widespread refugia/recolonization during major climate oscillations. We further identify a suite of genes potentially underpinning adaptations related to thermoregulation, oxygenation, diving, vision, diet, immunity and body size, which might have facilitated their remarkable secondary transition to an aquatic ecology. Our analyses indicate that penguins and their sister group (Procellariiformes) have the lowest evolutionary rates yet detected in birds. Together, these findings help improve our understanding of how penguins have transitioned to the marine environment, successfully colonizing some of the most extreme environments on Earth.
Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants ...influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.
We studied 15 men (8 treatment, 7 control) before and after 21 days of 6º head-down tilt to determine whether daily, 1-h exposures to 1.0 G
z
(at the heart) artificial gravity (AG) would prevent bed ...rest-induced cardiovascular deconditioning. Testing included echocardiographic analysis of cardiac function, plasma volume (PV), aerobic power (
V
O
2
pk) and cardiovascular and neuroendocrine responses to 80º head-up tilt (HUT). Data collected during HUT were ECG, stroke volume (SV), blood pressure (BP) and blood for catecholamines and vasoactive hormones. Heart rate (HR), cardiac output (CO), total peripheral resistance, and spectral power of BP and HR were calculated. Bed rest decreased PV, supine and HUT SV, and indices of cardiac function in both groups. Although PV was decreased in control and AG after bed rest, AG attenuated the decrease in orthostatic tolerance pre- to post-bed rest change; control: −11.8 ± 2.0, AG: −6.0 ± 2.8 min (
p
= 0.012) and
V
O
2
pk pre- to post-bed rest change; control: −0.39 ± 0.11, AG: −0.17 ± 0.06 L/min (
p
= 0.041). AG prevented increases in pre-tilt levels of plasma renin activity pre- to post-bed rest change; control: 1.53 ± 0.23, AG: −0.07 ± 0.34 ng/mL/h (
p
= 0.001) and angiotensin II pre- to post-bed rest change; control: 3.00 ± 1.04, AG: −0.63 ± 0.81 pg/mL (
p
= 0.009) and increased HUT aldosterone post-bed rest; control: 107 ± 30 pg/mL, AG: 229 ± 68 pg/mL (
p
= 0.045) and norepinephrine post-bed rest; control: 453 ± 107, AG: 732 ± 131 pg/mL (
p
= 0.003). We conclude that AG can mitigate some aspects of bed rest-induced cardiovascular deconditioning, including orthostatic intolerance and aerobic power. Mechanisms of improvement were not cardiac-mediated, but likely through improved sympathetic responsiveness to orthostatic stress.
The registration and certification of births has a wide array of individual and societal benefits. While near-universal in some parts of the world, birth registration is less common in many low- and ...middle-income countries, and the quality of vital statistics vary. We assembled publicly available birth registration records for as many countries as possible into a novel global birth registration database, and we present a systematic assessment of available data.
We obtained 4918 country-years of data from 145 countries covering the period 1948-2015. We compared these to existing estimates of total births to assess completeness of public data and adapted existing methods to evaluate the quality and timeliness of the data.
Since 1980, approximately one billion births were registered and shared in public databases. Compared to estimates of fertility, this represents only 40.0% of total births in the peak year, 2011. Approximately 74 million births (53.1%) per year occur in countries whose systems do not systematically register them and release the aggregate records. Considering data quality, timeliness, and completeness in country-years where data are available, only about 12 million births per year (8.6%) occur in countries with high-performing registration systems.
This analysis highlights the gaps in available data. Our objective and low-cost approach to assessing the performance of birth registration systems can be helpful to monitor country progress, and to help national and international policymakers set targets for strengthening birth registration systems.
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