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      Development of oil-based gels as versatile drug delivery systems for pediatric applications

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          Abstract

          Administering medicines to 0- to 5-year-old children in a resource-limited environment requires dosage forms that circumvent swallowing solids, avoid on-field reconstitution, and are thermostable, cheap, versatile, and taste masking. We present a strategy that stands to solve this multifaceted problem. As many drugs lack adequate water solubility, our formulations used oils, whose textures could be modified with gelling agents to form “oleogels.” In a clinical study, we showed that the oleogels can be formulated to be as fluid as thickened beverages and as stiff as yogurt puddings. In swine, oleogels could deliver four drugs ranging three orders of magnitude in their water solubilities and two orders of magnitude in their partition coefficients. Oleogels could be stabilized at 40°C for prolonged durations and used without redispersion. Last, we developed a macrofluidic system enabling fixed and metered dosing. We anticipate that this platform could be adopted for pediatric dosing, palliative care, and gastrointestinal disease applications.

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          Abstract

          We present molecular gastronomy–inspired dosage forms for administering medicines to children.

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          Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals

          Summary Background Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000–15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival. Methods We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1–59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation. Findings In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935–1·179]), pneumonia (0·921 million [0·812 −1·117]), and intrapartum-related events (0·691 million [0·598 −0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000–15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR. Interpretation In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target. Funding Bill & Melinda Gates Foundation, WHO.
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            A standardised static in vitro digestion method suitable for food - an international consensus.

            Simulated gastro-intestinal digestion is widely employed in many fields of food and nutritional sciences, as conducting human trials are often costly, resource intensive, and ethically disputable. As a consequence, in vitro alternatives that determine endpoints such as the bioaccessibility of nutrients and non-nutrients or the digestibility of macronutrients (e.g. lipids, proteins and carbohydrates) are used for screening and building new hypotheses. Various digestion models have been proposed, often impeding the possibility to compare results across research teams. For example, a large variety of enzymes from different sources such as of porcine, rabbit or human origin have been used, differing in their activity and characterization. Differences in pH, mineral type, ionic strength and digestion time, which alter enzyme activity and other phenomena, may also considerably alter results. Other parameters such as the presence of phospholipids, individual enzymes such as gastric lipase and digestive emulsifiers vs. their mixtures (e.g. pancreatin and bile salts), and the ratio of food bolus to digestive fluids, have also been discussed at length. In the present consensus paper, within the COST Infogest network, we propose a general standardised and practical static digestion method based on physiologically relevant conditions that can be applied for various endpoints, which may be amended to accommodate further specific requirements. A frameset of parameters including the oral, gastric and small intestinal digestion are outlined and their relevance discussed in relation to available in vivo data and enzymes. This consensus paper will give a detailed protocol and a line-by-line, guidance, recommendations and justifications but also limitation of the proposed model. This harmonised static, in vitro digestion method for food should aid the production of more comparable data in the future.
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              Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

              Summary Background Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. Methods We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15–60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. Findings Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5–24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates—a measure of relative inequality—increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7–87·2), and for men in Singapore, at 81·3 years (78·8–83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, and the gap between male and female life expectancy increased with progression to higher levels of SDI. Some countries with exceptional health performance in 1990 in terms of the difference in observed to expected life expectancy at birth had slower progress on the same measure in 2016. Interpretation Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age-specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled. Funding Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: InvestigationRole: ValidationRole: Writing - original draft
                Role: Data curationRole: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: Writing - review & editing
                Role: Formal analysisRole: Investigation
                Role: ResourcesRole: Validation
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: InvestigationRole: Resources
                Role: Investigation
                Role: InvestigationRole: Resources
                Role: InvestigationRole: ResourcesRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: Validation
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: VisualizationRole: Writing - original draft
                Role: InvestigationRole: Project administrationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: Validation
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                May 2022
                27 May 2022
                : 8
                : 21
                : eabm8478
                Affiliations
                [1 ]David H. Koch Institute for Integrative Cancer Research and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [2 ]Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
                [3 ]Sensory Spectrum Inc., New Providence, NJ 07974, USA.
                [4 ]Swiss Federal Institute of Technology (ETH), Zurich 8092, Switzerland.
                [5 ]Stonehill College, North Easton, MA 02357, USA.
                [6 ]University of Toronto, Toronto, ON, Canada.
                [7 ]Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
                [8 ]Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [9 ]Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                Author notes
                [* ]Corresponding author. Email: cgt20mit.edu, ctraverso@ 123456bwh.harvard.edu
                [†]

                These authors contributed equally to this work.

                [‡]

                Present address: Boeing Company, Herndon, VA 20170, USA.

                Author information
                https://orcid.org/0000-0002-3779-0363
                https://orcid.org/0000-0002-8648-1444
                https://orcid.org/0000-0001-9352-8370
                https://orcid.org/0000-0003-0632-4615
                https://orcid.org/0000-0002-3384-4109
                https://orcid.org/0000-0002-7693-0146
                https://orcid.org/0000-0001-7909-3294
                https://orcid.org/0000-0003-0894-296X
                https://orcid.org/0000-0003-0277-6120
                https://orcid.org/0000-0001-6849-4519
                https://orcid.org/0000-0003-4960-2216
                https://orcid.org/0000-0002-1071-5582
                https://orcid.org/0000-0003-2434-4978
                https://orcid.org/0000-0002-9581-8563
                https://orcid.org/0000-0003-4255-0492
                https://orcid.org/0000-0001-7851-4077
                Article
                abm8478
                10.1126/sciadv.abm8478
                9140966
                35622910
                08d5206b-fc2a-4094-8dee-28e7e00e400f
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                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 work is properly cited.

                History
                : 15 October 2021
                : 13 April 2022
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Applied Sciences and Engineering
                Life Sciences
                Life Sciences
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                Nicole Falcasantos

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