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The “highway to nowhere” is a 1.32 mile fragment of an arterial expressway located in Baltimore, Maryland. This segment was designed to contribute to a proposed limited access highway system that was never constructed after years of activism, debate, and lawsuits. This article examines the history of the construction of this highway segment to suggest that conflicts over the design, sitting, and construction of infrastructure are fundamentally struggles over the definition and production of space. This analysis utilizes Henri Lefebvre’s triad of spatial production as an analytical framework to identify distinct spatial forms that surface during the process of infrastructure building. Utilizing this analytical framework may enrich the STS-based infrastructure inquiries by bringing to the surface the multiple forms of spatial production that structure system-building activities. In conclusion, I suggest that utilizing Lefebvre’s triad within studies of infrastructure surfaces important, and potentially transformative, local claims to space. Such claims are of renewed importance as cities across the US confront the segregationist histories of the built environment.

Abstract Background The neighbor-joining method by Saitou and Nei is a widely used method for constructing phylogenetic trees. The formulation of the method gives rise to a canonical Θ(n3) algorithm upon which all existing implementations are based. Results In this paper we present techniques for speeding up the canonical neighbor-joining method. Our algorithms construct the same phylogenetic trees as the canonical neighbor-joining method. The best-case running time of our algorithms are O(n2) but the worst-case remains O(n3). We empirically evaluate the performance of our algoritms on distance matrices obtained from the Pfam collection of alignments. The experiments indicate that the running time of our algorithms evolve as Θ(n2) on the examined instance collection. We also compare the running time with that of the QuickTree tool, a widely used efficient implementation of the canonical neighbor-joining method. Conclusion The experiments show that our algorithms also yield a significant speed-up, already for medium sized instances.

Abstract Background Sucrose density gradient centrifugation and cross-flow filtration methods have been developed and standardised for the safe and reproducible production of inactivated arbovirus antigens which are appropriate for use in diagnostic serological applications. Methods To optimise the maximum titre of growth during the propagation of arboviruses, the multiplicity of infection and choice of cell line were investigated using stocks of Ross River virus and Barmah Forest virus grown in both mosquito and mammalian cell lines. To standardise and improve the efficacy of the inactivation of arboviral suspensions, stocks of Ross River virus, Barmah Forest virus, Japanese encephalitis virus, Murray Valley encephalitis virus and Alfuy virus were chemically inactivated using binary ethylenimine at a final concentration of 3 mM. Aliquots were then taken at hourly intervals and crude inactivation rates were determined for each virus using a plaque assay. To ensure complete inactivation, the same aliquots were each passaged 3 times in Aedes albopictus C6/36 cells and the presence of viral growth was detected using an immunofluorescent assay. For larger quantities of viral suspensions, centrifugation on an isopycnic sucrose density gradient or cross-flow filtration was used to produce concentrated, pure antigens or partially concentrated, semi-purified antigens respectively. Results The results of the propagation experiments suggested that the maximum viral titres obtained for both Ross River virus and Barmah Forest virus were affected by the incubation period and choice of cell line, rather than the use of different multiplicity of infection values. Results of the binary ethylenimine inactivation trial suggested that standardised periods of 5 or 8 hours would be suitable to ensure effective and complete inactivation for a number of different arboviral antigens. Conclusion Two methods used to prepare inactivated arbovirus antigens have been standardised to minimise production failure and expenditure and to provide reagents that conform to the highest quality and safety requirements of a diagnostic serology laboratory. The antigens are suitable for use in either enzyme linked immunosorbent assays or haemagglutination inhibition assays and the optimised protocols can be directly applied to produce antigens from new or emerging arboviral pathogens.

Applying a positive outlier lens is one effective approach for generating evidence to inform global health policy, program, and funding decisions. Exemplars in Global Health (EGH) is a program that studies positive outlier countries that have made extraordinary progress in health outcomes (despite limited resources) and disseminates their successes through multiple types of outputs. To date, EGH has studied, or is studying, 14 global health topics in 28 countries. This paper aims to identify findings, summarized as themes and sub-themes, that appear among all completed EGH studies. We developed a conceptual framework and used a content analysis approach to identify the top thematic areas that appear as drivers for programmatic success across EGH studies that were completed between June 2020-May 2023. The EGH studies (N = 31) spanned six topics including under-five child mortality (n = 6), childhood stunting (n = 5), community health workers (CHW) (n = 4), vaccine delivery (n = 3), COVID-19 response (n = 6), and newborn and maternal mortality reduction (n = 7) across 19 countries in sub-Saharan Africa, Latin America, South and Central Asia, and the Caribbean regions. Top drivers of success were defined as those critical or catalytic in achieving the intended outcome. Eight key drivers were identified: (1) efficient data collection and use for decision-making, (2) strong political commitment and health leadership, (3) effective stakeholder coordination, (4) a local, connected, and capacitated workforce, (5) intentional women's empowerment and engagement, (6) effective adoption and implementation of national policies, (7) effective and sustainable financing, and (8) equitable, efficient outreach and targeting. These cross-cutting drivers span a broad range of development outcomes, sectors, and populations, and indicate a need to effectively integrate people, systems, and sectors to improve global health outcomes. Findings from this study aim to support peer learning among countries and support evidence-based decision-making for funders, policymakers, and other key stakeholders., Competing Interests: This meta-analysis of completed research studies was funded by Gates Ventures, Seattle, WA. This does not alter our adherence to PLOS Global Public Health policies on sharing data and materials. There are no patents, products in development, or marketed products associated with this research to declare., (Copyright: © 2024 Akseer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset., (© 2024. The Author(s).)

Purpose: The genetic etiology of amyotrophic lateral sclerosis (ALS) includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both., Methods: 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by microarray genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS genome-wide association studies summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare-variant heterozygotes and non-heterozygotes., Results: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. Although ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed., Conclusion: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Although ethnicity is a key social determinant of health, there are no global analyses aimed at identifying countries that succeeded in reducing ethnic gaps in child health and nutrition., Methods: We identified 59 low and middle-income countries with at least two surveys since 2010 providing information on ethnicity or language and on three outcomes: under-five mortality, child stunting prevalence and a composite index (CCI) based on coverage with eight maternal and child health interventions. Firstly, we calculated population-weighted and unweighted measures of inequality among ethnic or language groups within each country. These included the mean difference from the overall national mean (absolute inequality), mean ratio relative to the overall mean (relative inequality), and the difference and ratio between the best- and worst-performing ethnic groups. Second, we examined annual changes in these measures in terms of annual absolute and relative changes. Thirdly, we compared trends for each of the three outcome indicators and identified exemplar countries with marked progress in reducing inequalities., Results: For each outcome indicator, annual changes in summary measures tended to show moderate (Pearson correlation coefficients of 0.4 to 0.69) or strong correlations (0.7 or higher) among themselves, and we thus focused on four of the 12 measures: absolute and relative annual changes in mean differences and ratios from the overall national mean. On average, absolute ethnic or language group inequalities tended to decline slightly for the three outcomes, and relative inequality declined for stunting and CCI, but increased for mortality. Correlations for annual trends across the three outcomes were inconsistent, with several countries showing progress in terms of one outcome but not in others. Togo and Uganda showed with the most consistent progress in reducing inequality, whereas the worst performers were Nigeria, Moldova, Kyrgyzstan, Sao Tome and Principe, and Burkina Faso., Conclusions: Although measures of annual changes in ethnic or language group inequalities in child health were consistently correlated within each outcome, analyses of such inequalities should rely upon multiple measures. Countries showing progress in one child health outcome did not necessarily show improvements in the remaining outcomes. In-depth analyses at country level are needed to understand the drivers of success in reducing ethnic gaps., (© 2023. The Author(s).)

Background: Understanding past successes in reaching unvaccinated or "zero-dose" children can help inform strategies for improving childhood immunization in other settings. Drawing from positive outlier methods, we developed a novel approach for identifying potential exemplars in reducing zero-dose children., Methods: Focusing on 2000-2019, we assessed changes in the percentage of under-one children with no doses of the diphtheria-tetanus-pertussis vaccine (no-DTP) across two geographic dimensions in 56 low- or lower-middle-income countries: (1) national levels; (2) subnational gaps, as defined as the difference between the 5th and 95th percentiles of no-DTP prevalence across second administrative units. Countries with the largest reductions for both metrics were considered positive outliers or potential 'exemplars', demonstrating exception progress in reducing national no-DTP prevalence and subnational inequalities. Last, so-called "neighborhood analyses" were conducted for the Gavi Learning Hub countries (Nigeria, Mali, Uganda, and Bangladesh), comparing them with countries that had similar no-DTP measures in 2000 but different trajectories through 2019., Results: From 2000 to 2019, the Democratic Republic of the Congo, Ethiopia, and India had the largest absolute decreases for the two no-DTP dimensions-national prevalence and subnational gaps-while Bangladesh and Burundi registered the largest relative reductions for each no-DTP metric. Neighborhood analyses highlighted possible opportunities for cross-country learning among Gavi Learning Hub countries and potential exemplars in reducing zero-dose children., Conclusions: Identifying where exceptional progress has occurred is the first step toward better understanding how such gains could be achieved elsewhere. Further examination of how countries have successfully reduced levels of zero-dose children-especially across variable contexts and different drivers of inequality-could support faster, sustainable advances toward greater vaccination equity worldwide.

Background: Indospicine is an arginine analogue and a natural toxin occurring only in Indigofera plant species, including Australian native species. It accumulates in the tissues of grazing animals, persisting for several months after ingestion. Dogs are particularly sensitive to indospicine toxicity and can suffer fatal liver disease after eating indospicine-contaminated pet meat., Method: A disease outbreak investigation was launched following notification to Agriculture Victoria of a cluster of 18 dogs displaying acute, severe, hepatopathy in the East Gippsland Shire in June 2021., Results: Between June and September 2021, 24 pet dogs died, and 40 others experienced liver disease after eating commercially prepared pet meat found to contain indospicine. The investigation identified the toxin in serum and liver samples from affected dogs and at high levels in some samples of pet meat eaten by the dogs. Twenty-six horses that were moved from the Northern Territory and processed at a Pet Meat Processing facility (knackery) in eastern Victoria over a period of 14 days in late May-early June 2021 were identified as the likely source of the indospicine toxin in the pet meat. Pet meat produced by the knackery and on-sold by several retailers was determined to be the cause of the illness and death in the dogs., Conclusion: This is the first report of severe and frequently fatal hepatopathy in dogs in Victoria relating to consumption of pet meat contaminated with indospicine., (© 2022 State of Victoria. Australian Veterinary Journal published by John Wiley & Sons Australia, Ltd on behalf of Australian Veterinary Association.)

Background: Variants in the ring finger protein 213 ( RNF213 ) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease., Methods: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology., Results: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines., Conclusions: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

Competing Interests: Competing interests: RAB, KAH and MCF are recipients of funding from the Bill & Melinda Gates Foundation. MCF is a recipient of funding from Gates Ventures and serves in an unpaid role on a Gates Ventures advisory board. NF, NG, GI and DEP are employees of Gates Ventures. NF received funding as a WHO consultant from June–September 2019. Authors declare no additional interests.

African Swine Fever (ASF) has been spreading in numerous southeast Asian countries since a major incursion in mainland China in 2018. Timor-Leste confirmed an outbreak of ASF in September 2019 which resulted in high mortalities in affected pigs. Pigs in Timor-Leste are the second most common type of livestock kept by villagers and represent a traditionally important source of income and prestige for householders. In order to understand the extent of ASF infected villages in Timor-Leste a prevalence survey was designed and conducted in November-December 2019. Timor-Leste has limited laboratory facilities and access to qPCR diagnostic tests. Therefore, a loop mediated isothermal amplification (LAMP) assay was used to detect ASF positive blood samples collected during the prevalence survey. The LAMP assay was proven to be a robust, highly specific and sensitive laboratory test for ASF suitable for use in the field and where there are limited laboratory facilities. The results of the prevalence survey allowed the extent of the ASF incursion to be delineated and the introduction of a disease response strategy to limit the spread of ASF and assist in the recovery of the pig population in Timor-Leste., Competing Interests: 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., (Copyright © 2021 Phillips, Mee, Lynch, da Conceição, Bendita da Costa Jong and Rawlin.)

Recent outbreaks of African swine fever virus (ASFV) have seen the movement of this virus into multiple new regions with devastating impact. Many of these outbreaks are occurring in remote, or resource-limited areas, that do not have access to molecular laboratories. Loop-mediated isothermal amplification (LAMP) is a rapid point of care test that can overcome a range of inhibitors. We outline further development of a real-time ASFV LAMP, including field verification during an outbreak in Timor-Leste. To increase field applicability, the extraction step was removed and an internal amplification control (IAC) was implemented. Assay performance was assessed in six different sample matrices and verified for a range of clinical samples. A LAMP detection limit of 400 copies/rxn was determined based on synthetic positive control spikes. A colourmetric LAMP assay was also assessed on serum samples. Comparison of the LAMP assay to a quantitative polymerase chain reaction (qPCR) was performed on clinical ASFV samples, using both serum and oral/rectal swabs, with a substantial level of agreement observed. The further verification of the ASFV LAMP assay, removal of extraction step, implementation of an IAC and the assessment of a range of sample matrix, further support the use of this assay for rapid in-field detection of ASFV.

Background: The Global Fund to Fight AIDS, Tuberculosis and Malaria was founded in 2002 as a public-private partnership between governments, the private sector, civil society, and populations affected by the three diseases. A key principle of the Global Fund is country ownership in accessing funding through "engagement of in-country stakeholders, including key and vulnerable populations, communities, and civil society." Research documenting whether diverse stakeholders are actually engaged and on how stakeholder engagement affects processes and outcomes of grant applications is limited., Objective: To examine representation during the 2017 Global Fund application process in the Democratic Republic of the Congo (DRC) and Uganda and the benefits and drawbacks of partnership to the process., Methods: We developed a mixed-methods social network survey to measure network structure and assess perceptions of how working together in partnership with other individuals/organizations affected perceived effectiveness, efficiency, and country ownership of the application process. Surveys were administered from December 2017-May 2018, initially to a set of central actors, followed by any individuals named during the surveys (up to 10) as collaborators. Network analyses were conducted using R., Findings: Collaborators spanning many organizations and expertise areas contributed to the 2017 applications (DRC: 152 nodes, 237 ties; Uganda: 118 nodes, 241 ties). Participation from NGOs and civil society representatives was relatively strong, with most of their ties being to different organization types, Uganda (63%), and DRC (67%), highlighting their collaborative efforts across the network. Overall, the perceived benefits of partnership were high, including very strong ratings for effectiveness in both countries. Perceived drawbacks of partnership were minimal; however, less than half of respondents thought partnership helped reduce transaction costs or financial costs, suggesting an inclusive and participatory process may come with short-term efficiency tradeoffs., Conclusions: Social network analysis can be useful for identifying who is included and excluded from the process, which can support efforts to ensure stronger, more meaningful engagement in future Global Fund application processes., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Introduction: Understanding how to deliver interventions more effectively is a growing emphasis in Global Health. Simultaneously, health system strengthening is a key component to improving delivery. As a result, it is challenging to evaluate programme implementation while reflecting real-world complexity. We present our experience in using a health systems modelling approach as part of a mixed-methods evaluation and describe applications of these models., Methods: We developed a framework for how health systems translate financial inputs into health outcomes, with in-country and international experts. We collated available data to measure framework indicators and developed models for malaria in Democratic Republic of the Congo (DRC), and tuberculosis in Guatemala and Senegal using Bayesian structural equation modelling. We conducted several postmodelling analyses: measuring efficiency, assessing bottlenecks, understanding mediation, analysing the cascade of care and measuring subnational effectiveness., Results: The DRC model indicated a strong relationship between shipment of commodities and utilisation thereof. In Guatemala, the strongest model coefficients were more evenly distributed. Results in Senegal varied most, but pathways related to community care had the strongest relationships. In DRC, we used model results to estimate the end-to-end cost of delivering commodities. In Guatemala, we used model results to identify potential bottlenecks and understand mediation. In Senegal, we used model results to identify potential weak links in the cascade of care, and explore subnationally., Conclusion: This study demonstrates a complementary modelling approach to traditional evaluation methods. Although these models have limitations, they can be applied in a variety of ways to gain greater insight into implementation and functioning of health service delivery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: The most common infection acquired in US hospitals is Clostridium difficile, which can lead to protracted diarrhea, severe abdominal cramping, and infectious colitis and an attributable mortality of 6.5%. The mortality associated with C. difficile is of major clinical importance. The best strategy to prevent such infections is an open question., Methods: A multiyear quality improvement initiative was performed in our community hospital to determine where hospitals should focus their resources to achieve sustainable reductions in hospital-acquired C. difficile infection (CDI). Quality improvement methodology was used to evaluate the impact of sequential interventions in environmental cleaning, infection prevention, and antibiotic stewardship over time., Results: After four years, hospital-acquired CDI declined 55.5%, from 12.2 to 5.4 cases/10,000 patient-days (Poisson rate test, p = 0.002). High-risk antibiotic use declined 88.1%, from 63.7 to 7.6 days on treatment/1,000 patient-days (Student's t-test, p < 0.001). The highest-impact intervention was stewardship on diagnostics and high-risk antibiotics using home-grown decision support tools., Conclusion: Translating scientific evidence into clinical practice using quality improvement methods led to sustained reductions in C. difficile transmission and identified high-risk antibiotics and diagnostics as key leverage points., (Copyright © 2018 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Improving childhood vaccine coverage is a priority for global health, but challenging in low and middle-income countries. Although previous research has sought to measure determinants of vaccination, most has limitations. We measure determinants using a clearly-defined hypothetical model, multi-faceted data, and modeling strategy that makes full use of the hypothesis and data., Methods: We use linked, cross-sectional survey data from households, health facilities, patients and health offices in Uganda and Zambia, and Bayesian Structural Equation Modeling to quantify the proportion of variance in childhood vaccination that is explained by key determinants, controlling for known confounding., Results: We find evidence that the leading determinant of vaccination is different for different outcomes. For three doses of pentavalent vaccine, intent to vaccinate (on the part of the mother) is the leading driver, but for one dose of the vaccine, community access is a larger factor. For pneumococcal conjugate vaccine, health facility readiness is the leading driver. Considering specifically-modifiable determinants, improvements in cost, facility catchment populations and staffing would be expected to lead to the largest increase in coverage according to the model., Conclusions: This analysis measures vaccination determinants using improved methods over most existing research. It provides evidence that determinants should be approached in the context of relevant outcomes, and evidence of specific determinants that could have the greatest impact in these two countries, if targeted. Future studies should seek to improve our analytic framework, apply it in different settings, and utilize stronger study designs. Programs that focus on a particular determinant should use these results to select an outcome that is appropriate to measure their effectiveness. Vaccination programs in these countries should use our findings to better target interventions and continue progress against vaccine preventable diseases., (Copyright © 2018. Published by Elsevier Ltd.)

Old World species of Leishmania typically cause visceral and cutaneous leishmaniasis. Mucosal involvement is typically seen with infection by Leishmania species found in South America, usually after the healing of cutaneous leishmaniasis. We present five imported cases of mucosal leishmaniasis caused by Old World Mediterranean Leishmania infantum exclusively affecting the nasal mucosa or vocal cord. In only one case was there a recollection of a preceding cutaneous lesion compatible with cutaneous Leishmaniasis. Of significance was that four out of five cases were receiving local corticosteroids for chronic lung disorders and four were systemically immunosuppressed. This report highlights the importance of considering mucosal leishmaniasis in the differential diagnosis in those presenting with upper respiratory tract mucosal lesions with a relevant travel history to the Mediterranean and in whom malignancy has been excluded.

Background: Many children in low and middle-income countries remain unvaccinated, and vaccines do not always produce immunity. Extensive research has sought to understand why, but most studies have been limited in breadth and depth. This study documents existing evidence on determinants of vaccination and immunization and presents a conceptual framework of determinants., Methods: We used systematic review, content analysis, thematic analysis and interpretive synthesis to document and analyze the existing evidence on determinants of childhood vaccination and immunization., Results: We documented 1609 articles, including content analysis of 78 articles. Three major thematic models were described in the context of one another. Interpretive synthesis identified similarities and differences between studies, resulting in a conceptual framework with three principal vaccine utilization determinants: 1) Intent to Vaccinate, 2) Community Access and 3) Health Facility Readiness., Conclusion: This study presents the most comprehensive systematic review of vaccine determinants to date. The conceptual framework represents a synthesis of multiple existing frameworks, is applicable in low and middle-income countries, and is quantitatively testable. Future researchers can use these results to develop competing conceptual frameworks, or to analyze data in a theoretically-grounded way. This review enables better research in the future, further understanding of immunization determinants, and greater progress against vaccine preventable diseases around the world.

Bridging the 'know-do gap' is an enormous challenge for global health practitioners. They must be able to understand local health dynamics within the operational and social contexts that engender them, test and adjust approaches to implementation in collaboration with communities and stakeholders, interpret data to inform policy decisions, and design adaptive and resilient health systems at scale. These skills and methods have been formalized within the nascent field of Implementation Science (IS). As graduates of the world's first PhD program dedicated explicitly to IS, we have a unique perspective on the value of IS and the training, knowledge, and skills essential to bridging the 'know-do gap'. In this article, we describe the philosophy and curricula at the core of our program, outline the methods vital to IS in a global health context, and detail the role that we believe IS will increasingly play in global health practice. At this junction of enormous challenges and opportunities, we believe that IS offers the necessary tools for global health professionals to address complex problems in context and raises the bar of success for the global health programs of the future., Competing Interests: and funding The authors have not received any funding or benefits from industry or elsewhere to conduct this study.

Background: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development., Methods: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time., Findings: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries., Interpretation: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions., Funding: Bill & Melinda Gates Foundation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration., Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets., Findings: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990., Interpretation: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action., Funding: Bill & Melinda Gates Foundation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Timely and reliable data on causes of death are fundamental for informed decision-making in the health sector as well as public health research. An in-depth understanding of the quality of data from vital statistics (VS) is therefore indispensable for health policymakers and researchers. We propose a summary index to objectively measure the performance of VS systems in generating reliable mortality data and apply it to the comprehensive cause of death database assembled for the Global Burden of Disease (GBD) 2013 Study., Methods: We created a Vital Statistics Performance Index, a composite of six dimensions of VS strength, each assessed by a separate empirical indicator. The six dimensions include: quality of cause of death reporting, quality of age and sex reporting, internal consistency, completeness of death reporting, level of cause-specific detail, and data availability/timeliness. A simulation procedure was developed to combine indicators into a single index. This index was computed for all country-years of VS in the GBD 2013 cause of death database, yielding annual estimates of overall VS system performance for 148 countries or territories., Results: The six dimensions impacted the accuracy of data to varying extents. VS performance declines more steeply with declining simulated completeness than for any other indicator. The amount of detail in the cause list reported has a concave relationship with overall data accuracy, but is an important driver of observed VS performance. Indicators of cause of death data quality and age/sex reporting have more linear relationships with simulated VS performance, but poor cause of death reporting influences observed VS performance more strongly. VS performance is steadily improving at an average rate of 2.10% per year among the 148 countries that have available data, but only 19.0% of global deaths post-2000 occurred in countries with well-performing VS systems., Conclusions: Objective and comparable information about the performance of VS systems and the utility of the data that they report will help to focus efforts to strengthen VS systems. Countries and the global health community alike need better intelligence about the accuracy of VS that are widely and often uncritically used in population health research and monitoring.

Purpose: In this article, the authors report a case of acquired stuttering associated with Parkinson's disease (PD) that was responsive to unilateral subthalamic nucleus deep-brain stimulation (STN DBS) in the language-dominant hemisphere., Method: A single-subject, masked, multiple baseline design was used to evaluate the effects of unilateral left STN DBS on stuttering associated with PD. The patient underwent 3 formal speech assessments of spontaneous speech and the reading of passages with DBS off and on. Speech samples were videotaped and placed in random order, and 2 independent speech-language pathologists calculated the percentage of stuttered syllables and classified individual stuttering events., Results: Stuttering improved significantly in the DBS-on condition. In total, 10% of syllables were affected by stuttering events with DBS off, and less than 1% of syllables were affected by stuttering events with DBS on (n = 2,281 syllables, p < .00001, in a chi(2) test). The effect of unilateral STN DBS on stuttering was relatively independent of whether the patient was on or off dopaminergic medications., Conclusion: This article emphasizes the important role of the subthalamic region in the motor control of speech and language.

We demonstrate that first-order light shifts can be canceled for an all-optical, three-photon-absorption resonance (N-resonance) on the D1 transition of 87Rb. This light-shift cancellation facilitates improved frequency stability for an N-resonance clock. For example, by using a tabletop apparatus designed for N-resonance spectroscopy, we measured a short-term fractional frequency stability (Allan deviation) of approximately/= 1.5 x 10(-11) tao1/2 for observation times of 1 s < or = tao < or = 50 s. Further improvements in frequency stability should be possible with an apparatus designed as a dedicated N-resonance clock.

Prostaglandins and leukotrienes are implicated in conditions of both the upper and lower airways. In the former they are deranged in nasal polyposis, intrinsic rhinitis and allergic rhinitis while in the latter they are involved in the pathogenesis of asthma. The aim of the present study was to measure mucosal eicosanoid levels in the three types of rhinitis and compare with controls. In addition, the effect of topical steroids on eicosanoid levels in rhinitis was examined. The levels of prostaglandins E(2) (PGE(2)) and D(2) (PGD(2)) and of leukotrienes E(4) (LTE(4)) and B(4) (LTB(4)) were measured in nasal biopsies from the inferior turbinates of patients suffering from perennial rhinitis and a control group. Rhinitis patients were classified into three categories: perennial allergic rhinitis (PAR), non-allergic rhinitis with eosinophilia (NARES) and noneosinophilic non-allergic rhinitis (NENAR) on the basis of symptoms, secretion eosinophilia, nasal resistance and allergy testing. Patients with rhinitis were randomized into two groups. One received fluticasone propionate nasal spray (FPANS) and the other a placebo (PNS) over a period of six weeks prior to the biopsies. One hundred and one patients with PAR, NARES or NENAR were recruited sequentially and the control group consisted of 21 patients with no evidence of rhinitis but with nasal obstruction due to septal deviation. Untreated rhinitics had significantly lower levels of PGE(2), PGD(2) and LTE(4) than non-rhinitic controls. Six-weeks' treatment with FPANS significantly increased the levels of those eicosanoids in patients with PAR and NARES but they were still significantly below normal. Levels of LTB(4) in all three rhinitis groups were not significantly different from controls and treatment with topical steroids had no effect. Their findings are contrary to current thinking that increased levels of eicosanoids, in particular cysteinyl-leukotrienes, play an important role in the pathogenesis of chronic, non-infective upper airway inflammation.