Comparison of oral nifedipine and oral labetalol as a single drug therapy for control of blood pressure in preeclampsia

Background: Worldwide hypertension during pregnancy is a common cause of maternal and fetal morbidity and mortality. Effective control of blood pressure is one of the important steps in management of preeclampsia. Few drugs like nifedipine, labetalol, methyldopa, and hydralazine have acceptable high safety profile during pregnancy.Methods: In this study 120 antenatal women with non-severe preeclampsia were compared by giving either nifedipine or labetalol as a single drug therapy for control of blood pressure. Various parameters like control of blood pressure, side effects of drugs, gestational age at the time of delivery, mode of delivery, any complication and perinatal outcome were assessed.Results: In this study authors found that in both group, adequate control of blood pressure was achieved. This study shows slightly higher rate of pre term delivery and LSCS with labetalol and minimal side effects with nifedipine but difference in each group is insignificant.Conclusions: Labetalol and nifedipine both the drugs are equally effective in reducing blood pressure and any of it can safely be used as a first choice of drug for management of hypertension in preeclampsia and it can be decided as per clinician’s experience and familiarity with drug

Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016

The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030

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

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, an

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation

Step-wise differentiation of cerebral organoids towards hippocampal and choroid plexus progeny by sustained expression of early NSC stage-specific microRNA-20b

Pluripotent stem cells (PSCs) have the ability to undergo indefinite self-renewal while giving rise to the three germ layers. This remarkable capacity has turned PSCs to be a fundamental cell source for regenerative medicine research and applications. The derivation of induced pluripotent stem cells (iPSCs) over a decade ago has sparked a widespread enthusiasm and opportunity for personalized autologous cell-based therapies in a wide array of diseases. However, the development of optimized disease models and iPSC-derived products heavily relies on the generation of homogenous culture systems for the cell type of interest, which currently presents one of the major hindrances towards the use of PSC derivatives in therapeutic applications. The cerebral cortex is an excellent example of a tissue with enormous heterogeneity that introduces immense challenges for in vitro disease models and therapeutic applications. Our lab mainly focuses on studying the development of the cerebral cortex, particularly investigating the development of cortical neural stem cells (NSCs). Our goal is to devise approaches for the differentiation of PSCs into founder NSC building blocks. We put particular emphasis on achieving high purity that will enable studying authentic cell fate decisions that are associated with regional patterning, self-renewal and differentiation processes that shape the cortex. A homogeneous early cortical population will also enable extracting a more reliable molecular identity of those cells, which can then be used for meaningful disease modeling and for devising sophisticated approaches to induce or maintain self-renewal of such populations in vitro. However, recent research from our lab has shown that current methods to derive early cortical progenitors from PSCs are highly diverse and yield heterogeneous populations containing both cortical and non-cortical cell types. This results in heterogeneous founder NSC populations, limiting their use as a universal pure NSC source. To overcome this hurdle, our lab established a streamlined method known as Triple-i paradigm to derive homogenous starting cortical progenitors both in neural rosettes (2D) and in organoids (3D) platforms. The main objectives of this thesis are to identify early signals that modulate temporal and regional fates within developing founder cortical NSC populations, focusing on small non-coding RNA (miRNAs), which are known to be key regulators of many developmental processes including stem cell proliferation and lineage specifications. These miRNAs guide the early development in a spatiotemporal manner by regulating the expression of multiple gene networks at the post-transcriptional level. They are abundantly expressed in the developing neural tube that eventually gives rise to different regions of central nervous system, including the cerebral cortex. However, it is unknown whether they have the capacity to specify a particular brain region in the cortex such as archicortex that consists of cortical hem, hippocampus and choroid plexus. In this study, we have identified a miRNA important for the specification of archicortex and interrogated its role in cell fate specification using a battery of molecular and cellular studies. First, we employed in vitro human embryonic stem cell-based models (2D monolayer and 3D cerebral organoid) for the derivation of founder neural stem cell and their progression. We then identified a list of miRNAs that are specifically expressed in this early neural stem cell stage, among which we found hsa-miR-20b-5p to be one of the highly expressed microRNAs in early NSCs derived under both monolayer culture and cerebral organoids. Second, by overexpressing hsa-miR-20b-5p in cerebral organoids, we provided evidence that this miRNA is involved in the stepwise specification of choroid plexus of archicortex, by caudalizing the early cortical NSC, due to modulation of WNT and BMP signalling components. In addition, cellular immunostainings displayed a characteristic presence of giant but thin single- layer vesicles positive for choroid plexus markers in miR-20b overexpressing organoids, as opposed to pseudostratified cortical neural rosettes in wildtype organoids. Furthermore, we showed that co-overexpression of miR-20b with of its main target CCND1, lead to the generation of cortical hem/hippocampus organoids. Altogether, through an extensive miRNA-sequencing, single cell RNA-sequencing and cellular immunofluorescence studies, we revealed the expression of hsa-miR-20b-5p in early neural stem cells, its role in the specification of the archicortex lineages and its part as a cell fate modulator for converting cortical organoids towards choroid plexus structures.Pluripotente Stammzellen (PSCs) haben die Fähigkeit, sich auf unbestimmte Zeit selbst zu erneuern und dabei die drei Keimblätter hervorzubringen. Diese bemerkenswerte Fähigkeit hat PSCs zu einer grundlegenden Zellquelle für die Forschung und Anwendungen der regenerativen Medizin gemacht. Die Gewinnung von induzierten pluripotenten Stammzellen (iPSCs) vor über einem Jahrzehnt hat eine weit verbreitete Begeisterung geweckt und Möglichkeiten für personalisierte autologe zellbasierte Therapien bei einer Vielzahl von Krankheiten aufgedeckt. Die Entwicklung optimierter Krankheitsmodelle und von iPSC abgeleiteter Produkte hängt jedoch stark von der Erzeugung homogener Kultursysteme für den bestimmten Zelltyp ab, was derzeit eines der Haupthindernisse für den Einsatz von PSC-Derivaten in therapeutischen Anwendungen darstellt. Die Großhirnrinde ist ein hervorragendes Beispiel für ein Gewebe mit enormer Heterogenität, das für In-vitro-Krankheitsmodelle und therapeutische Anwendungen immense Herausforderungen mit sich bringt. Unser Labor konzentriert sich hauptsächlich auf die Untersuchung der Entwicklung der Großhirnrinde, insbesondere der Entwicklung von kortikalen neuralen Stammzellen (NSCs). Unser Ziel ist es, Ansätze zur Differenzierung von PSCs in Gründer-NSC-Bausteine zu entwickeln. Wir legen besonderen Wert darauf, eine hohe Reinheit zu erreichen, die es ermöglicht, authentische Entscheidungen über das Zellschicksal zu untersuchen, die mit den regionalen Mustern, Selbsterneuerung und Differenzierungsprozessen verbunden sind, die den Kortex formen. Eine homogene frühe kortikale Population wird es auch ermöglichen, eine zuverlässigere molekulare Identität dieser Zellen zu bestimmen, die dann für aussagekräftige Krankheitsmodelle und für die Entwicklung fortgeschrittener Ansätze zur Induktion oder Aufrechterhaltung der Selbsterneuerung solcher Populationen in vitro verwendet werden kann. Jüngste Forschungen aus unserem Labor haben jedoch gezeigt, dass aktuelle Methoden zur Ableitung früher kortikaler Vorläufer aus PSCs sehr vielfältig sind und heterogene Populationen ergeben, die sowohl kortikale als auch nicht-kortikale Zelltypen enthalten. Dies führt zu heterogenen Gründer-NSC-Populationen, die nur beschränkt als universelle reine NSC-Quelle dienen können. Um diese Hürde zu überwinden, hat unser Labor eine optimierte Methode namens Triple-i-Paradigma entwickelt, um homogene kortikale Ausgangsvorläufer sowohl in neuronalen Rosetten (2D) als auch in Organoiden (3D) abzuleiten. Die Hauptziele dieser Arbeit sind die Identifizierung von frühen Signalen, die zeitliche und regionale Schicksale innerhalb sich entwickelnder kortikaler NSC-Populationen modulieren. Dabei liegt der Fokus auf kleinen nicht-kodierenden RNAs (miRNAs), die wichtige Regulatoren vieler Entwicklungsprozesse sind, wie Stammzellproliferation und Zelltyp-Spezifizierung. Diese miRNAs steuern die frühe Entwicklung in Raum und Zeit, indem sie die Expression mehrerer Gennetzwerke auf posttranskriptioneller Ebene regulieren. Sie werden reichlich im sich entwickelnden Neuralrohr exprimiert, aus dem schließlich verschiedene Regionen des zentralen Nervensystems, einschließlich der Großhirnrinde, hervorgehen. Es ist jedoch nicht bekannt, ob sie in der Lage sind, eine bestimmte Hirnregion im Kortex zu spezifizieren, wie z.B. den Archicortex, der aus kortikalem Saum, Hippocampus und Plexus choroideus besteht. In dieser Studie haben wir eine miRNA identifiziert, die für die Spezifikation des Archicortex wichtig ist, und ihre Rolle bei der Spezifikation des Zellschicksals mit einer Reihe von molekularen und zellulären Studien untersucht. Zunächst verwendeten wir in vitro-Modelle auf der Basis von humanen embryonalen Stammzellen (2D-Monolayer und 3D-zerebrales Organoid) zur Ableitung von neuralen Gründerstammzellen und deren Progression. Wir identifizierten eine Reihe miRNAs, die spezifisch in diesem frühen neuralen Stammzellstadium exprimiert werden. Unter anderem identifizierten wir hsa-miR-20b-5p als eine der hochexprimierten miRNAs in frühen NSCs, die entweder aus Monolayer-Kulturen oder zerebralen Organoiden stammen. Zweitens lieferten wir durch die Überexpression von hsa-miR-20b-5p in zerebralen Organoiden den Nachweis, dass diese miRNA an der schrittweisen Spezifizierung des Plexus choroideus des Archicortex beteiligt ist, indem sie die frühen kortikalen NSC durch die Modulation von WNT- und BMP-Signalkomponenten kaudalisiert. Darüber hinaus zeigten zelluläre Immunfärbungen ein charakteristisches Vorhandensein von riesigen, aber dünnen einschichtigen Vesikeln, die – im Gegensatz zu pseudostratifizierten kortikalen neuralen Rosetten in Wildtyp-Organoiden – positiv für Plexus choroideus-Marker in miR-20b-überexprimierenden Organoiden waren. Darüber hinaus haben wir gezeigt, dass die Ko-Überexpression von miR-20b mit seinem Hauptziel CCND1 zur Bildung von kortikalen Hem-/Hippocampus-Organoiden führt. Insgesamt haben wir durch umfangreiche miRNA-Sequenzierung, Einzelzell-RNA-Sequenzierung und zelluläre Immunfluoreszenzstudien die Expression von hsa-miR-20b-5p in frühen neuralen Stammzellen, seine Rolle bei der Spezifizierung der Archicortex-Linien und seine Rolle als Zellschicksalsmodulator zur Umwandlung von kortikalen Organoiden in Strukturen des Plexus choroideus aufgedeckt