Summary Measurements of health indicators are rarely available for every population and period of interest, and available data may not be comparable. The Guidelines for Accurate and Transparent ...Health Estimates Reporting (GATHER) define best reporting practices for studies that calculate health estimates for multiple populations (in time or space) using multiple information sources. Health estimates that fall within the scope of GATHER include all quantitative population-level estimates (including global, regional, national, or subnational estimates) of health indicators, including indicators of health status, incidence and prevalence of diseases, injuries, and disability and functioning; and indicators of health determinants, including health behaviours and health exposures. GATHER comprises a checklist of 18 items that are essential for best reporting practice. A more detailed explanation and elaboration document, describing the interpretation and rationale of each reporting item along with examples of good reporting, is available on the GATHER website.
Achieving universal health coverage, including quality essential service coverage and financial protection for all, is target 3.8 of the Sustainable Development Goals (SDG). As a result, an index of ...essential health service coverage indicators was selected by the UN as SDG indicator 3.8.1. We have developed an index for measuring SDG 3.8.1, describe methods for compiling the index, and report baseline results for 2015.
16 tracer indicators were selected for the index, which included four from within each of the categories of reproductive, maternal, newborn, and child health; infectious disease; non-communicable diseases; and service capacity and access. Indicator data for 183 countries were taken from UN agency estimates or databases, supplemented with submissions from national focal points during a WHO country consultation. The index was computed using geometric means, and a subset of tracer indicators were used to summarise inequalities.
On average, countries had primary data since 2010 for 72% of the final set of indicators. The median national value for the service coverage index was 65 out of 100 (range 22–86). The index was highly correlated with other summary measures of health, and after controlling for gross national income and mean years of adult education, was associated with 21 additional years of life expectancy over the observed range of country values. Across 52 countries with sufficient data, coverage was 1% to 66% lower among the poorest quintile as compared with the national population. Sensitivity analyses suggested ranks implied by the index are fairly stable across alternative calculation methods.
Service coverage within universal health coverage can be measured with an index of tracer indicators. Our universal health coverage service coverage index is simple to compute by use of available country data and can be refined to incorporate relevant indicators as they become available through SDG monitoring.
Ministry of Health, Japan, and the Rockefeller Foundation.
To estimate cause-of-death distributions in the early (0-6 days of age) and late (7-27 days of age) neonatal periods, for 194 countries between 2000 and 2013.
For 65 countries with high-quality vital ...registration, we used each country's observed early and late neonatal proportional cause distributions. For the remaining 129 countries, we used multinomial logistic models to estimate these distributions. For countries with low child mortality we used vital registration data as inputs and for countries with high child mortality we used neonatal cause-of-death distribution data from studies in similar settings. We applied cause-specific proportions to neonatal death estimates from the United Nations Inter-agency Group for Child Mortality Estimation, by country and year, to estimate cause-specific risks and numbers of deaths.
Over time, neonatal deaths decreased for most causes. Of the 2.8 million neonatal deaths in 2013, 0.99 million deaths (uncertainty range: 0.70-1.31) were estimated to be caused by preterm birth complications, 0.64 million (uncertainty range: 0.46-0.84) by intrapartum complications and 0.43 million (uncertainty range: 0.22-0.66) by sepsis and other severe infections. Preterm birth (40.8%) and intrapartum complications (27.0%) accounted for most early neonatal deaths while infections caused nearly half of late neonatal deaths. Preterm birth complications were the leading cause of death in all regions of the world.
The neonatal cause-of-death distribution differs between the early and late periods and varies with neonatal mortality rate level. To reduce neonatal deaths, effective interventions to address these causes must be incorporated into policy decisions.
It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure ...prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.
Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.
We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
Zero-dose prevalence refers to children who failed to receive any routine vaccination. Little is known about the “immunisation cascade” in low- and middle-income countries (LMICs), defined as how ...children move from zero dose to full immunisation.
Using data from national surveys carried out in 92 LMICs since 2010 and focusing on the four basic vaccines delivered in infancy (BCG, polio, DPT and MCV), we describe zero-dose prevalence and the immunisation cascade in children aged 12 to 23 months. We also describe the most frequent combinations of vaccines (or co-coverage) among children who are partially immunized. Analyses are stratified by country income groups, household wealth quintiles derived from asset indices, sex of the child and area of residence. Results were pooled across countries using child populations as weights.
In the 92 countries, 7.7% were in the zero-dose group, and 3.3%, 3.4% and 14.6% received one, two or three vaccines, respectively; 70.9% received the four types and 59.9% of the total were fully immunised with all doses of the four vaccines. Three quarters (76.8%) of children who received the first vaccine received all four types. Among children with a single vaccine, polio was the most common in low- and lower-middle income countries, and BCG in upper-middle income countries. There were sharp inequalities according to household wealth, with zero-dose prevalence ranging from 12.5% in the poorest to 3.4% in the wealthiest quintile across all countries. The cascades were similar for boys and girls. In terms of dropout, 4% of children receiving BCG did not receive DPT1, 14% receiving DPT1 did not receive DPT3, and 9% receiving DPT3 did not progress to receive MCV.
Interpretation.
Focusing on zero-dose children is particularly important because those who are reached with the first vaccine are highly likely to also receive remaining vaccines.
The eukaryotic genome is packaged into chromatin. The nucleosome, the basic unit of chromatin, is composed of DNA coiled around a histone octamer. Histones are among the longest-lived protein species ...in mammalian cells due to their thermodynamic stability and their associations with DNA and histone chaperones. Histone metabolism plays an integral role in homeostasis. While histones are largely stable, the degradation of histone proteins is necessary under specific conditions. Here, we review the physiological and cellular contexts that promote histone degradation. We describe specific known mechanisms that drive histone proteolysis. Finally, we discuss the importance of histone degradation and regulation of histone supply for organismal and cellular fitness.
HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ...ART are urgently needed. Here, we demonstrate that CD4+ T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4+ lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.
Chromosomal instability (CIN) is a hallmark of many cancers. Restricting the localization of centromeric histone H3 variant CENP-A to centromeres prevents CIN. CENP-A overexpression (OE) and ...mislocalization have been observed in cancers and correlate with poor prognosis; however, the molecular consequences of CENP-A OE on CIN and aneuploidy have not been defined. Here, we show that CENP-A OE leads to its mislocalization and CIN with lagging chromosomes and micronuclei in pseudodiploid DLD1 cells and xenograft mouse model. CIN is due to reduced localization of proteins to the kinetochore, resulting in defects in kinetochore integrity and unstable kinetochore-microtubule attachments. CENP-A OE contributes to reduced expression of cell adhesion genes and higher invasion of DLD1 cells. We show that CENP-A OE contributes to aneuploidy with karyotypic heterogeneity in human cells and xenograft mouse model. In summary, our results provide a molecular link between CENP-A OE and aneuploidy, and suggest that karyotypic heterogeneity may contribute to the aggressive phenotype of CENP-A-overexpressing cancers.
Estimating the required sample size and statistical power for a study is an integral part of study design. For standard designs, power equations provide an efficient solution to the problem, but they ...are unavailable for many complex study designs that arise in practice. For such complex study designs, computer simulation is a useful alternative for estimating study power. Although this approach is well known among statisticians, in our experience many epidemiologists and social scientists are unfamiliar with the technique. This article aims to address this knowledge gap.
We review an approach to estimate study power for individual- or cluster-randomized designs using computer simulation. This flexible approach arises naturally from the model used to derive conventional power equations, but extends those methods to accommodate arbitrarily complex designs. The method is universally applicable to a broad range of designs and outcomes, and we present the material in a way that is approachable for quantitative, applied researchers. We illustrate the method using two examples (one simple, one complex) based on sanitation and nutritional interventions to improve child growth.
We first show how simulation reproduces conventional power estimates for simple randomized designs over a broad range of sample scenarios to familiarize the reader with the approach. We then demonstrate how to extend the simulation approach to more complex designs. Finally, we discuss extensions to the examples in the article, and provide computer code to efficiently run the example simulations in both R and Stata.
Simulation methods offer a flexible option to estimate statistical power for standard and non-traditional study designs and parameters of interest. The approach we have described is universally applicable for evaluating study designs used in epidemiologic and social science research.
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