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Competing Interests: We declare no competing interests. This work is supported by the Bill & Melinda Gates Foundation (INV-038624 and OPP1172551 to LL and REB). FV acknowledges funding from the Spanish State Research Agency under the Ramón y Cajal programme (RYC2021-033979-I).

Background: Reliable and rigorously collected sexual, reproductive, maternal, newborn, child, and adolescent (SRMNCAH) data from humanitarian settings are often sparse and variable in quality across different settings due to the lack of a standardised set of indicators across the different agencies working in humanitarian settings. This paper aims to summarise a WHO-led global initiative to develop and scale up an SRMNCAH monitoring and evaluation framework for humanitarian settings., Methods: This research revolved around three phases. The first and the last phase involved global consultations with lead international agencies active in SRMNCAH in humanitarian settings. The second phase tested the feasibility of the proposed indicators in Afghanistan, Bangladesh, the Democratic Republic of the Congo, and Jordan, using different qualitative research methods (interviews with 92 key informants, 26 focus group discussions with 142 key stakeholders, facility assessments and observations at 25 health facilities or sites)., Results: Among the 73 proposed indicators, 47 were selected as core indicators and 26 as additional indicators. Generally, there were no major issues in collecting the proposed indicators, except for those indicators that relied on death reviews or population-level data. Service availability and morbidity indicators were encouraged. Abortion and SGBV indicators were challenging to collect due to political and sociocultural reasons. The HIV and PMTCT indicators were considered as core indicators, despite potential sensitivity in some settings. Existing data collection and reporting systems across the four assessed humanitarian settings were generally fragmented and inconsistent, mainly attributed to the lack of coordination among different agencies., Interpretation: Implementing agencies need to collaborate effectively to scale up this agreed-upon set of SRMNCAH framework to enhance accountability and transparency in humanitarian settings., (© 2022 Published by Elsevier Inc.)

Background: There are currently no global recommendations on a parsimonious and robust set of indicators that can be measured routinely or periodically to monitor quality of hospital care for children and young adolescents. We describe a systematic methodology used to prioritize and define a core set of such indicators and their metadata for progress tracking, accountability, learning and improvement, at facility, (sub) national, national, and global levels., Methods: We used a deductive methodology which involved the use of the World Health Organization Standards for improving the quality-of-care for children and young adolescents in health facilities as the organizing framework for indicator development. The entire process involved 9 complementary steps which included: a rapid literature review of available evidence, the application of a peer-reviewed systematic algorithm for indicator systematization and prioritization, and multiple iterative expert consultations to establish consensus on the proposed indicators and their metadata., Results: We derived a robust set of 25 core indicators and their metadata, representing all 8 World Health Organization quality standards, 40 quality statements and 520 quality measures. Most of these indicators are process-related (64%) and 20% are outcome/impact indicators. A large proportion (84%) of indicators were proposed for measurement at both outpatient and inpatient levels. By virtue of being a parsimonious set and given the stringent criteria for prioritizing indicators with "quality measurement" attributes, the recommended set is not evenly distributed across the 8 quality standards., Conclusions: To support ongoing global and national initiatives around paediatric quality-of-care programming at country level, the recommended indicators can be adopted using a tiered approach that considers indicator measurability in the short-, medium-, and long-terms, within the context of the country's health information system readiness and maturity. However, there is a need for further research to assess the feasibility of implementing these indicators across contexts, and the need for their validation for global common reporting., (© 2022. The Author(s).)

Nurturing care encompasses five components that are crucial for supporting early childhood development: good health, adequate nutrition, opportunities for early learning, responsive caregiving, and safety and security. While there has been increasing attention in global public health towards designing and delivering programs, services, and policies to promote nurturing care, measurement has focused more on the components of health and nutrition, with less attention to early learning, responsive caregiving, and safety and security. We conducted a scoping review to identify articles that measured at least one nurturing care outcome in a sample of caregivers and/or children under-5 years of age in low- and middle-income countries (LMICs). We systematically searched five electronic bibliographic databases for peer-reviewed articles published from database inception until November 30, 2020. We first classified outcomes to their respective nurturing care component, and then applied an inductive approach to organize key constructs within each nurturing care component and the specific measures and indicators used across studies. We identified 239 total articles representing more than 50 LMICs for inclusion in the review. The majority of included studies reported a measure of nutrition (N = 166), early learning (N = 140), and health (N = 102), followed by responsive caregiving (N = 78) and lastly safety and security (N = 45). For each nurturing care component, we uncovered multiple constructs relevant to children under-5: nutrition (e.g., anthropometry, complementary feeding), early learning (e.g., stimulation practices, early childhood education), health (e.g., birth outcomes, morbidity), responsive caregiving (e.g., parental responsivity, parent-child interactions), and safety and security (e.g., discipline, inadequate supervision). Particularly for outcomes of early learning and responsive caregiving, there was greater variability with regards to the measures used, reported indicators, and analytic construction of variables than the other three nurturing care components. This study provides a comprehensive review of the current state of measurement of nurturing care. Additional research is needed in order to establish the most optimal measures and indicators for assessing nurturing care, especially for early learning and responsive caregiving., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Jeong 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.)

Background: Investments in the survival of older children and adolescents (aged 5-19 years) bring triple dividends for now, their future, and the next generation. However, 1·5 million deaths occurred in this age group globally in 2019, nearly all from preventable causes. To better focus the attention of the global community on improving survival of children and adolescents and to guide effective policy and programmes, sound and timely cause of death data are crucial, but often scarce., Methods: In this systematic analysis, we provide updated time-series for 2000-19 of national, regional, and global cause of death estimates for 5-19-year-olds with age-sex disaggregation. We estimated separately for countries with high versus low mortality, by data availability, and for four age-sex groups (5-9-year-olds [both sexes], 10-14-year-olds [both sexes], 15-19-year-old females, and 15-19-year-old males). Only studies reporting at least two causes of death were included in our analysis. We obtained empirical cause of death data through systematic review, known investigator tracing, and acquisition of known national and subnational cause of death studies. We adapted the Bayesian Least Absolute Shrinkage and Selection Operator approach to address data scarcity, enhance covariate selection, produce more robust estimates, offer increased flexibility, allow country random effects, propagate coherent uncertainty, and improve model stability. We harmonised all-cause mortality estimates with the UN Inter-agency Group for Child Mortality Estimation and systematically integrated single cause estimates as needed from WHO and UNAIDS., Findings: In 2019, the global leading specific causes of death were road traffic injuries (115 843 [95% uncertainty interval 110 672-125 054] deaths; 7·8% [7·5-8·1]); neoplasms (95 401 [90 744-104 812]; 6·4% [6·1-6·8]); malaria (81 516 [72 150-94 477]; 5·5% [4·9-6·2]); drowning (77 460 [72 474-85 952]; 5·2% [4·9-5·5]); and diarrhoea (72 679 [66 599-82 002], 4·9% [4·5-5·3]). The leading causes varied substantially across regions. The contribution of communicable, maternal, perinatal, and nutritional conditions declined with age, whereas the number of deaths associated with injuries increased. The leading causes of death were diarrhoea (51 630 [47 206-56 235] deaths; 10·0% [9·5-10·5]) in 5-9-year-olds; malaria (31 587 [23 940-43 116]; 8·6% [6·6-10·4]) in 10-14-year-olds; self-harm (32 646 [29 530-36 416]; 13·4% [12·6-14·3]) in 15-19-year-old females; and road traffic injuries (48 757 [45 692-52 625]; 13·9% [13·3-14·3]) in 15-19-year-old males. Widespread declines in cause-specific mortality were estimated across age-sex groups and geographies in 2000-19, with few exceptions like collective violence., Interpretation: Child and adolescent survival needs focused attention. To translate the vision into actions, more investments in the health information infrastructure for cause of death and in the related life-saving interventions are needed., Funding: Bill & Melinda Gates Foundation and WHO., Competing Interests: Declaration of interests LL, FV, DY, JP, and REB report grants from the Bill & Melinda Gates Foundation. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019., Methods: We updated cause-specific mortality estimates for neonates and children aged 1-59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis., Findings: In 2019, there were 5·30 million deaths (95% uncertainty range 4·92-5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1-19·5), lower respiratory infections (13·9%, 12·0-15·1), intrapartum-related events (11·6%, 10·6-12·5), and diarrhoea (9·1%, 7·9-9·9), with 49·2% (47·3-51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4-25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality., Interpretation: Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death., Funding: Bill & Melinda Gates Foundation; WHO., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The Sustainable Development Goals (SDGs), set in 2015 by the UN General Assembly, call for all countries to reach an under-5 mortality rate (U5MR) of at least as low as 25 deaths per 1000 livebirths and a neonatal mortality rate (NMR) of at least as low as 12 deaths per 1000 livebirths by 2030. We estimated levels and trends in under-5 mortality for 195 countries from 1990 to 2019, and conducted scenario-based projections of the U5MR and NMR from 2020 to 2030 to assess country progress in, and potential for, reaching SDG targets on child survival and the potential under-5 and neonatal deaths over the next decade., Methods: Levels and trends in under-5 mortality are based on the UN Inter-agency Group for Child Mortality Estimation (UN IGME) database on under-5 mortality, which contains around 18 000 country-year datapoints for 195 countries-nearly 10 000 of those datapoints since 1990. The database includes nationally representative mortality data from vital registration systems, sample registration systems, population censuses, and household surveys. As with previous sets of national UN IGME estimates, a Bayesian B-spline bias-reduction model (B3) that considers the systematic biases associated with the different data source types was fitted to these data to generate estimates of under-5 (age 0-4 years) mortality with uncertainty intervals for 1990-2019 for all countries. Levels and trends in the neonatal mortality rate (0-27 days) are modelled separately as the log ratio of the neonatal mortality rate to the under-5 mortality rate using a Bayesian model. Estimated mortality rates are combined with livebirths data to calculate the number of under-5 and neonatal deaths. To assess the regional and global burden of under-5 deaths in the present decade and progress towards SDG targets, we constructed several scenario-based projections of under-5 mortality from 2020 to 2030 and estimated national, regional, and global under-5 mortality trends up to 2030 for each scenario., Findings: The global U5MR decreased by 59% (90% uncertainty interval [UI] 56-61) from 93·0 (91·7-94·5) deaths per 1000 livebirths in 1990 to 37·7 (36·1-40·8) in 2019, while the annual number of global under-5 deaths declined from 12·5 (12·3-12·7) million in 1990 to 5·2 (5·0-5·6) million in 2019-a 58% (55-60) reduction. The global NMR decreased by 52% (90% UI 48-55) from 36·6 (35·6-37·8) deaths per 1000 livebirths in 1990, to 17·5 (16·6-19·0) in 2019, and the annual number of global neonatal deaths declined from 5·0 (4·9-5·2) million in 1990, to 2·4 (2·3-2·7) million in 2019, a 51% (47-54) reduction. As of 2019, 122 of 195 countries have achieved the SDG U5MR target, and 20 countries are on track to achieve the target by 2030, while 53 will need to accelerate progress to meet the target by 2030. 116 countries have reached the SDG NMR target with 16 on track, leaving 63 at risk of missing the target. If current trends continue, 48·1 million under-5 deaths are projected to occur between 2020 and 2030, almost half of them projected to occur during the neonatal period. If all countries met the SDG target on under-5 mortality, 11 million under-5 deaths could be averted between 2020 and 2030., Interpretation: As a result of effective global health initiatives, millions of child deaths have been prevented since 1990. However, the task of ending all preventable child deaths is not done and millions more deaths could be averted by meeting international targets. Geographical and economic variation demonstrate the possibility of even lower mortality rates for children under age 5 years and point to the regions and countries with highest mortality rates and in greatest need of resources and action., Funding: Bill & Melinda Gates Foundation, US Agency for International Development., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Effective coverage measures aim to estimate the proportion of a population in need of a service that received a positive health outcome. In 2020, the Effective Coverage Think Tank Group recommended using a 'coverage cascade' for maternal, newborn, child and adolescent health and nutrition (MNCAHN), which organises components of effective coverage in a stepwise fashion, with each step accounting for different aspects of quality of care (QoC), applied at the population level. The cascade outlines six steps that increase the likelihood that the population in need experience the intended health benefit: 1) the population in need (target population) who contact a health service; 2) that has the inputs available to deliver the service; 3) who receive the health service; 4) according to quality standards; 5) and adhere to prescribed medication(s) or health workers instructions; and 6) experience the expected health outcome. We examined how effective coverage of life-saving interventions from childbirth to children aged nine has been defined and assessed which steps of the cascade are captured by existing measures., Methods: We undertook a rapid systematic review. Seven scientific literature databases were searched covering the period from May 1, 2017 to July, 8 2021. Reference lists from reviews published in 2018 and 2019 were examined to identify studies published prior to May 2017. Eligible studies reported population-level contact coverage measures adjusted for at least one dimension of QoC., Results: Based on these two search approaches this review includes literature published from 2010 to 2021. From 16 662 records reviewed, 33 studies were included, reporting 64 effective coverage measures. The most frequently examined measures were for childbirth and immediate newborn care (n = 24). No studies examined measures among children aged five to nine years. Definitions of effective coverage varied across studies. Key sources of variability included (i) whether a single effective coverage measure was reported for a package of interventions or separate measures were calculated for each intervention; (ii) the number and type of coverage cascade steps applied to adjust for QoC; and (iii) the individual items included in the effective coverage definition and the methods used to generate a composite quality measure., Conclusion: In the MNCAHN literature there is substantial heterogeneity in both definitions and construction of effective coverage, limiting the comparability of measures over time and place. Current measurement approaches are not closely aligned with the proposed cascade. For widespread adoption, there is a need for greater standardisation of indicator definitions and transparency in reporting, so governments can use these measures to improve investments in MNACHN and implement life-saving health policies and programs., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Introduction: In 2019, over 70 million people were forcibly displaced worldwide. Women and girls comprise nearly half of this population and are at heightened risk of negative sexual and reproductive health outcomes. With the collapse of health systems, reduced resources and increased vulnerabilities from displacement, there is a need to strengthen current practices and ensure the delivery of comprehensive sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) services. Recognising the need for consistency in data collection, analysis and use, the WHO developed a list of core SRMNCAH monitoring and evaluation indicators for services and outcomes in humanitarian settings. This research will explore the feasibility of collecting this core set of SRMNCAH indicators in displacement contexts., Methods and Analysis: We will undertake a multimethods qualitative study in seven humanitarian settings: Afghanistan, Albania, Bangladesh, Cameroon, the Democratic Republic of the Congo, Iraq and Jordan. We selected sites that reflect diversity in geographic region, sociocultural characteristics, primary location(s) of displaced persons and nature and phase of the crisis. Our study consists of four components: key informant interviews, facility assessments, observational sessions at select facilities and focus group discussions with front-line healthcare personnel. We will analyse our data using descriptive statistics and for content and themes. We will begin by analysing data from each setting separately and will then combine these data to explore concordant and discordant results, triangulate findings and develop global recommendations., Ethics and Dissemination: The University of Ottawa's Research Ethics Board and the Research Project Review Panel (RP 2) of the World Health Organization-Department of Sexual and Reproductive Health as well as local IRBs of PIs' research institutions reviewed and approved this protocol. We intend to disseminate findings through workshops at the WHO country, regional and headquarter levels, as well as through local, national and international conferences, workshops, peer-reviewed publications, and reports., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The 2030 Sustainable Development Goals agenda calls for health data to be disaggregated by age. However, age groupings used to record and report health data vary greatly, hindering the harmonisation, comparability, and usefulness of these data, within and across countries. This variability has become especially evident during the COVID-19 pandemic, when there was an urgent need for rapid cross-country analyses of epidemiological patterns by age to direct public health action, but such analyses were limited by the lack of standard age categories. In this Personal View, we propose a recommended set of age groupings to address this issue. These groupings are informed by age-specific patterns of morbidity, mortality, and health risks, and by opportunities for prevention and disease intervention. We recommend age groupings of 5 years for all health data, except for those younger than 5 years, during which time there are rapid biological and physiological changes that justify a finer disaggregation. Although the focus of this Personal View is on the standardisation of the analysis and display of age groups, we also outline the challenges faced in collecting data on exact age, especially for health facilities and surveillance data. The proposed age disaggregation should facilitate targeted, age-specific policies and actions for health care and disease management., Competing Interests: We declare no competing interests., (© 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY-NC-ND 3.0 IGO license.)

The under-5 mortality rate has declined from 93 deaths per 1000 live births in 1990 to 39 per 1000 live births in 2018. This improvement in child survival warrants an examination of age-specific trends and causes of death over time and across regions and an extension of the survival focus to older children and adolescents. We examine patterns and trends in mortality for neonates, postneonatal infants, young children, older children, young adolescents and older adolescents from 2000 to 2016. Levels and trends in causes of death for children and adolescents under 20 years of age are based on United Nations Inter-agency Group for Child Mortality Estimation for all-cause mortality, the Maternal and Child Epidemiology Estimation group for cause of death among children under-5 and WHO Global Health Estimates for 5-19 year-olds. From 2000 to 2016, the proportion of deaths in young children aged 1-4 years declined in most regions while neonatal deaths became over 25% of all deaths under 20 years in all regions and over 50% of all under-5 deaths in all regions except for sub-Saharan Africa which remains the region with the highest under-5 mortality in the world. Although these estimates have great variability at the country level, the overall regional patterns show that mortality in children under the age of 5 is increasingly concentrated in the neonatal period and in some regions, in older adolescents. The leading causes of disease for children under-5 remain preterm birth and infectious diseases, pneumonia, diarrhoea and malaria. For older children and adolescents, injuries become important causes of death as do interpersonal violence and self-harm. Causes of death vary by region., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

N -Methyl-d-aspartate receptors (NMDARs) are ionotropic ligand-gated glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system (CNS). Several neurological disorders may involve NMDAR hypofunction, which has driven therapeutic interest in positive allosteric modulators (PAMs) of NMDAR function. Here we describe modest changes to the tetrahydroisoquinoline scaffold of GluN2C/GluN2D-selective PAMs that expands activity to include GluN2A- and GluN2B-containing recombinant and synaptic NMDARs. These new analogues are distinct from GluN2C/GluN2D-selective compounds like (+)-(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1 H )-yl)methanone (CIQ) by virtue of their subunit selectivity, molecular determinants of action, and allosteric regulation of agonist potency. The ( S )-enantiomers of two analogues (EU1180-55, EU1180-154) showed activity at NMDARs containing all subunits (GluN2A, GluN2B, GluN2C, GluN2D), whereas the ( R )-enantiomers were primarily active at GluN2C- and GluN2D-containing NMDARs. Determination of the actions of enantiomers on triheteromeric receptors confirms their unique pharmacology, with greater activity of ( S ) enantiomers at GluN2A/GluN2D and GluN2B/GluN2D subunit combinations than ( R ) enantiomers. Evaluation of the ( S )-EU1180-55 and EU1180-154 response of chimeric kainate/NMDA receptors revealed structural determinants of action within the pore-forming region and associated linkers. Scanning mutagenesis identified structural determinants within the GluN1 pre-M1 and M1 regions that alter the activity of ( S )-EU1180-55 but not ( R )-EU1180-55. By contrast, mutations in pre-M1 and M1 regions of GluN2D perturb the actions of only the ( R )-EU1180-55 but not the ( S ) enantiomer. Molecular modeling supports the idea that the ( S ) and ( R ) enantiomers interact distinctly with GluN1 and GluN2 pre-M1 regions, suggesting that two distinct sites exist for these NMDAR PAMs, each of which has different functional effects.

Essential health, education and other service disruptions arising from the COVID-19 pandemic risk reversing some of the hard-won gains in improving child survival over the past 40 years. Although children have milder symptoms of COVID-19 disease than adults, pandemic control measures in many countries have disrupted health, education and other services for children, often leaving them without access to birth and postnatal care, vaccinations and early childhood preventive and treatment services. These disruptions mean that the SARS-CoV-2 virus, along with climate change and shifting epidemiological and demographic patterns, are challenging the survival gains that we have seen over the past 40 years. We revisit the initiatives and actions of the past that catalyzed survival improvements in an effort to learn how to maintain these gains even in the face of today's global challenges.

The N -methyl-d-aspartate receptor (NMDAR) is an ion channel that mediates the slow, Ca 2+ -permeable component of glutamatergic synaptic transmission in the central nervous system (CNS). NMDARs are known to play a significant role in basic neurological functions, and their dysfunction has been implicated in several CNS disorders. Herein, we report the discovery of second-generation GluN2C/D-selective NMDAR-positive allosteric modulators (PAMs) with a dihydropyrrolo[1,2- a ]pyrazin-3(4 H )-one core. The prototype, R -(+)-EU-1180-453 , exhibits log unit improvements in the concentration needed to double receptor response, lipophilic efficiency, and aqueous solubility, and lowers cLogP by one log unit compared to the first-generation prototype CIQ . Additionally, R -(+)-EU-1180-453 was found to increase glutamate potency 2-fold, increase the response to maximally effective concentration of agonist 4-fold, and the racemate is brain-penetrant. These compounds are useful second-generation in vitro tools and a promising step toward in vivo tools for the study of positive modulation of GluN2C- and GluN2D-containing NMDA receptors.

Intervention coverage-the proportion of the population with a health-care need who receive care-does not account for intervention quality and potentially overestimates health benefits of services provided to populations. Effective coverage introduces the dimension of quality of care to the measurement of intervention coverage. Many definitions and methodological approaches to measuring effective coverage have been developed, resulting in confusion over definition, calculation, interpretation, and monitoring of these measures. To develop a consensus on the definition and measurement of effective coverage for maternal, newborn, child, and adolescent health and nutrition (MNCAHN), WHO and UNICEF convened a group of experts, the Effective Coverage Think Tank Group, to make recommendations for standardising the definition of effective coverage, measurement approaches for effective coverage, indicators of effective coverage in MNCAHN, and to develop future effective coverage research priorities. Via a series of consultations, the group recommended that effective coverage be defined as the proportion of a population in need of a service that resulted in a positive health outcome from the service. The proposed effective coverage measures and care cascade steps can be applied to further develop effective coverage measures across a broad range of MNCAHN services. Furthermore, advances in measurement of effective coverage could improve monitoring efforts towards the achievement of universal health coverage., (Copyright © 2020 This is an Open Access article published under the CC BY-NC-ND 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: This article is part of a series proposed by Countdown to 2030 for Women’s, Children’s and Adolescents’ Health and the Partnership for Maternal, Newborn and Child Health (PMNCH) hosted by the World Health Organization and commissioned by The BMJ, which peer reviewed, edited, and made the decisions to publish. Open access fees are funded by the Bill and Melinda Gates Foundation and PMNCH.

Subnational inequalities have received limited attention in the monitoring of progress towards national and global health targets during the past two decades. Yet, such data are often a critical basis for health planning and monitoring in countries, in support of efforts to reach all with essential interventions. Household surveys provide a rich basis for interventions coverage indicators on reproductive, maternal, newborn and child health (RMNCH) at the country first administrative level (regions or provinces). In this paper, we show the large subnational inequalities that exist in RMNCH coverage within 39 countries in sub-Saharan Africa, using a composite coverage index which has been used extensively by Countdown to 2030 for Women's, Children's and Adolescent's Health. The analyses show the wide range of subnational inequality patterns such as low overall national coverage with very large top inequality involving the capital city, intermediate national coverage with bottom inequality in disadvantaged regions, and high coverage in all regions with little inequality. Even though nearly half of the 34 countries with surveys around 2004 and again around 2015 appear to have been successful in reducing subnational inequalities in RMNCH coverage, the general picture shows persistence of large inequalities between subnational units within many countries. Poor governance and conflict settings were identified as potential contributing factors. Major efforts to reduce within-country inequalities are required to reach all women and children with essential interventions., 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.)

Health facility data are a critical source of local and continuous health statistics. Countries have introduced web-based information systems that facilitate data management, analysis, use and visualisation of health facility data. Working with teams of Ministry of Health and country public health institutions analysts from 14 countries in Eastern and Southern Africa, we explored data quality using national-level and subnational-level (mostly district) data for the period 2013-2017. The focus was on endline analysis where reported health facility and other data are compiled, assessed and adjusted for data quality, primarily to inform planning and assessments of progress and performance. The analyses showed that although completeness of reporting was generally high, there were persistent data quality issues that were common across the 14 countries, especially at the subnational level. These included the presence of extreme outliers, lack of consistency of the reported data over time and between indicators (such as vaccination and antenatal care), and challenges related to projected target populations, which are used as denominators in the computation of coverage statistics. Continuous efforts to improve recording and reporting of events by health facilities, systematic examination and reporting of data quality issues, feedback and communication mechanisms between programme managers, care providers and data officers, and transparent corrections and adjustments will be critical to improve the quality of health statistics generated from health facility data., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: With global survival increasing for children younger than 5 years of age, attention is required to reduce the approximately 1 million deaths of children aged 5-14 years occurring every year. Causes of death at these ages remain poorly documented. We aimed to explore trends in mortality by causes of death in India, China, Brazil, and Mexico, which are home to about 40% of the world's children aged 5-14 years and experience more than 200 000 deaths annually at these ages., Methods: We examined data on 244 401 deaths in children aged 5-14 years from four nationally representative data sources that obtained direct distributions of causes of death: the Indian Million Death Study, the Chinese Disease Surveillance Points, mortality data from the Mexican Instituto Nacional de Estadística y Geografía, and mortality data from the Brazilian Institute of Geography and Statistics. We present data on 12 main disease groups in all countries, with breakdown by communicable and nutritional diseases, non-communicable diseases, injuries, and ill-defined causes. To calculate age-specific and sex-specific death rates for each cause, we applied the national cause of death distribution to the UN mortality envelopes for 2005-16 for each country., Findings: Unlike Brazil, China, and Mexico, communicable diseases still account for nearly half of deaths in India in children aged 5-14 years (73 920 [46·1%] of 160 330 estimated deaths in 2016). In 2016, India had the highest death rates in nearly every category, including from communicable diseases. Fast declines among girls in communicable disease mortality narrowed the gap by 2016 with boys in India (32·6 deaths per 100 000 girls vs 26·2 per 100 000 boys) and China (1·7 vs 1·5). In China, injuries accounted for the greatest proportions of deaths (20 970 [53·2%] of 39 430 estimated deaths, in which drowning was a leading cause). The homicide death rate at ages 10-14 years was higher for boys than for girls in Brazil, increasing annually by an average of 0·7% (0·3-1·1). In India and China, the suicide death rates were higher for girls than for boys at ages 10-14 years. By contrast, in Mexico it was higher for boys than for girls, increasing annually by an average of 2·8% (2·0-3·6). Deaths from transport injuries, drowning, and cancer are common in all four countries, with transport accidents among the top three causes of death for both sexes in all countries, except for Indian girls, and cancer in the top three causes for both sexes in Mexico, Brazil, and China., Interpretation: Most of the deaths that occurred between 2005 and 2016 in children aged 5-14 years in India, China, Brazil, and Mexico arose from preventable or treatable conditions. This age group is important for extending some of the global disease-specific targets developed for children younger than 5 years of age. Interventions to control non-communicable diseases and injuries and to strengthen cause of death reporting systems are also required., Funding: WHO and the University of Toronto Connaught Global Challenge., (© This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

N -methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist. Multiple compounds potentiate the response of NMDARs with submicromolar EC 50 values. Analysis of enantiomeric pairs revealed that the S-(-) enantiomer is active at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the R-(+) enantiomer is only active at GluN2C/D subunits. These results provide a starting point for the development of selective positive allosteric modulators for GluN2B-containing receptors.

Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function., (Copyright © 2016 American Society of Human Genetics. All rights reserved.)

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d-/- mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (+)-CIQ potentiation and was not accelerated in slices from Grin2d-/- mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing., (U.S. Government work not protected by U.S. copyright.)

Lesbian, gay, bisexual, and transgender (LGBT) patients experience barriers to health care that include fear of discrimination, as well as insensitivity and lack of knowledge about LGBT-specific health needs among providers. This study examined the effectiveness of an educational intervention designed to improve knowledge and attitudes of baccalaureate nursing students regarding LGBT patient care. Education focused on key terminology, health disparities, medical needs of transgender patients, and culturally sensitive communication skills for competent LGBT patient care. Knowledge level and attitudes were evaluated before and after the intervention using a survey based on a modified Attitudes Toward Lesbians and Gay Men Scale and two assessment tools developed for this study. A statistically significant increase in positive attitudes and knowledge level was found immediately after the intervention. Findings from this study support the inclusion of education related to LGBT patient health care in undergraduate nursing curricula to promote cultural competence and sensitivity., (Copyright 2015, SLACK Incorporated.)

Introduction: The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are capable of regulating the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA intersubunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor., Areas Covered: This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor., Expert Opinion: The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics.

We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline-containing analogs. Compounds were evaluated using both two-electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits AMPA, kainate, and GABA or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors.

Introduction: The NMDA receptor is a ligand-gated ion channel that plays a critical role in higher level brain processes and has been implicated in a range of neurological and psychiatric conditions. Although initial studies for the use of NMDA receptor antagonists in neuroprotection were unsuccessful, more recently, NMDA receptor antagonists have shown clinical promise in other indications such as Alzheimer's disease, Parkinson's disease, pain and depression. Based on the clinical observations and more recent insights into receptor pharmacology, new modulatory approaches are beginning to emerge, with potential therapeutic benefit., Areas Covered: The article covers the known pharmacology and important features regarding NMDA receptors and their function. A discussion of pre-clinical and clinical relevance is included, as well. The subsequent patent literature review highlights the current state of the art targeting the receptor since the last review in 2010., Expert Opinion: The complex nature of the NMDA receptor structure and function is becoming better understood. As knowledge about this receptor increases, it opens up new opportunities for targeting the receptor for many therapeutic indications. New strategies and advances in older technologies will need to be further developed before clinical success can be achieved. First-in-class potentiators and subunit-selective agents form the basis for most new strategies, complemented by efforts to limit off-target liability and fine-tune on-target properties.

Objectives: The WHO Global InfoBase assembles country-level chronic disease risk factor prevalence data from WHO's member states., Methods: The focus of this report is recent, nationally representative data. The risk factors of choice are those that make the greatest contribution to mortality and morbidity from chronic disease, can be changed through primary intervention and are easily measured in populations., Results: Eight risk factors fit these criteria. They are: tobacco and alcohol use, patterns of physical inactivity, low fruit/vegetable intake, obesity, blood pressure, cholesterol and diabetes. Important to the data collection is the need to display prevalence data for these eight risk factors by age group(s) and sex and with some measure of the uncertainty of the estimate., Conclusions: This tool can be used by countries to evaluate the quality of the data that they have for chronic disease surveillance. The aim is to improve risk factor data quality and to standardize data, either through common survey instruments or by using existing country data to model risk factor estimates. These "harmonized" estimates will allow for comparisons over time and between countries.

The pharmacokinetics and bioavailability of L-751,164, an ethyl ester prodrug of a potent fibrinogen receptor antagonist, L-742,998, were studied in beagle dogs and rhesus monkeys. In both species, L-751,164 exhibited high clearance. After an intravenous dose, L-751,164 was converted to the parent L-742,998 to the extent of approximately 20% in dogs and 90% in monkeys. After oral administration of the prodrug, however, the bioavailability, measured either as the prodrug or as the active parent, was < 5% in both species. Several experiments were conducted subsequently to investigate possible causes for the observed similarities in the low oral bioavailability of the prodrug between species despite its differences in the in vivo conversion. In vitro metabolism studies using dog liver subcellular fractions indicated extensive metabolism of L-751,164 to metabolites other than L-742,998. Kinetically, L-742,998 formation accounted only for approximately 25% of the prodrug disappearance. In contrast, monkey liver preparations converted L-751,164 exclusively and rapidly to L-742,998. Good agreement between the in vitro hepatic metabolism and the in vivo observations suggests that liver was the major eliminating organ after intravenous administration of the prodrug in both species. In dogs, this suggestion was further supported by low bioavailability of the prodrug (20%) and the parent (below detection limit) after intraportal administration of the prodrug. In vitro metabolism of L-751,164 using intestinal S9 fractions revealed substantial metabolism in monkeys, but not in dogs. Several NADPH-dependent metabolites were observed with monkey intestinal preparation, with the parent L-742,998 being the minor product (approximately 25-30%). Furthermore, L-751,164 was shown, by means of an in vitro Caco-2 cell, and in situ rat intestinal loop models, to be highly permeable to intestinal barriers. Collectively, these results suggest that the apparent species differences in the prodrug conversion observed in vivo likely were due to species differences in the hepatic metabolism of the prodrug. In both species, the high first-pass metabolism of the prodrug, and the extensive conversion of the prodrug to metabolic products other than the parent contributed, at least in part, to the low bioavailability of the prodrug and active parent, respectively, obtained after an oral dose of the prodrug. The latter process was species-dependent, involving primarily the hepatic first-pass elimination in dogs and the intestinal first-pass metabolism in monkeys.