Investigating local circuit function following spinal cord injury and cell transplant therapy

Spinal cord injury (SCI) leads to severe functional deficits and currently there are no effective treatments. In addition to the initial mechanical damage to axons, neurons and glia, traumatic injury also triggers a complex array of cellular and molecular events. Some of these processes are thought to contribute to mechanisms of progressive damage (secondary mechanisms) whilst others concurrently promote limited repair. Functional outcome depends on the interaction of these two processes. However, the interacting dynamics and time course with which they impact the functional outcome is not fully understood. Secondary processes are studied with molecular and anatomical approaches and loss of axons or neurons are used to infer reduced function. Similarly, recovery of functional outcome is mostly assessed using behavioural approaches. However, these are unable to differentiate recovery due to compensatory plastic changes in the brain which might contribute to recovery. Therefore, the first aim of the thesis was to develop an electrophysiological approach to directly assess functional changes in spinal cord circuits following a contusion SCI. The second aim was to use this protocol combined with behavioural testing in order to investigate the use of human embryonic stem cell derived mesenchymal stem cells (hESC-MSCs) as a potential therapy for spinal cord injury. An electrophysiological approach was used to assess spinal cord function after contusion injuries at the cervical (C6) level of the rat spinal cord. Contusion injuries due to high velocity impact were made using an Infinite Horizon Impactor device. Cord dorsum potentials (CDPs) evoked by supramaximal electrical stimulation of a radial nerve (to activate sensory fibres) or within the pyramids (to activate corticospinal fibres) were used to measure changes in the function of these fibre systems in the vicinity of the injury. Animals were investigated at different time points from acute up to 6 months post injury to characterise the temporal progression of changes in spinal cord function. Contusion injury produced an immediate substantial reduction in sensory circuit function which was highly localized to the site of the impact. However, CDPs continued to be evoked both above and below the injury site. This suggests that the main sensory axons in the dorsal column which carry impulses past the level of the injury are not substantially affected and deterioration of function at the injury centre is a result of damage to the neurons and axon collaterals located at the site of impact. Further worsening occurred over the following 3 days but was more marked above the level of the injury possibly because it is due to demyelination of the main sensory axons. However, CDP mapping at 2 weeks showed almost complete recovery of the potentials above this compared to 3 days reflecting a repair mechanism which is possibly remyelination. The fact that CDP amplitudes at 2 weeks are very close to those recorded immediately after injury suggests that most of the loss of function produced by the contusion is due to primary mechanical trauma and that secondary mechanisms contribute relatively little to the loss of function. CDP amplitudes recorded 4 weeks, 7 weeks and 3 months after injury remained closely similar to 2 weeks suggesting a prolonged period of stability in the sensory system. However, a later phase of deterioration is observed at 6 months below the injury possibly due to extension of the injury cavity causing further neuronal loss. Histology also revealed significantly larger cavities in 6 month survival animals. CDPs evoked by stimulation of the corticospinal tract below the injury level were profoundly depressed immediately following a contusion reflecting extensive damage to the main component of the CST in the dorsal columns while potentials above the injury were not acutely affected. There was a further reduction in CDP amplitudes rostral to the injury at 3 days due to demyelination or die back of CST fibres in the dorsal columns. Substantially this improved at 2 weeks and then remained stable up to 6 months. Below the injury there was a gradual increase in the strength of corticospinal connections evident by an increase in CDP amplitudes at 7 weeks which was maximal by 3 months. This reflects plasticity in the spared corticospinal projection probably those in the lateral component. Mesenchymal stem cells (MSCs) from bone marrow (BM) have been reported to promote repair and some functional improvement in animal models. However, autologous transplantation of BM-MSCs has several disadvantages such as the need for invasive harvesting, variable cell quality and slow proliferation. We have successfully derived MSC-like cells from human embryonic stem cells (hESCs) and have found that these cells show anatomical evidence of repair after transplantation in an animal model of SCI (Mohamad, 2014). Delayed transplants of hESC derived MSCs (hESC-MSCs) were performed in a cervical (C6) contusion (175 kdyn) injury model. These cells were transplanted 3 weeks after injury and immunosuppression was begun two days prior to this and continued for the remainder of the study. Functional outcomes were evaluated behaviourally using grip strength and horizontal ladder walking to assess improvement in forelimb function. In electrophysiology experiments cord dorsum potentials (CDPs) evoked by supra-maximal electrical stimulation of a radial nerve or within the pyramids were used to measure changes in the function of these fibre systems in the vicinity of a spinal cord injury at 7 weeks post-transplant. There was a substantial reduction in the gripping ability immediately after the contusion injury followed by a modest spontaneous recovery. Weekly assessment of the grip strength score before and after transplantation revealed no differences in hESC-MSC transplanted and control groups of animals. Similarly, ladder walk analysis revealed loss of co-ordinated forelimb-hindlimb stepping and increased errors of forepaw placement on the ladder rungs after injury. There was no difference in the recovery of co-ordination or improvement of forelimb function after hESC-MSC transplants compared to control animals. Similarly, terminal electrophysiological experiments showed that the amplitudes of CDPs evoked by radial nerve stimulation were closely similar at all recording locations in both groups of animals. However, corticospinal evoked CDPs showed deterioration of function in the transplanted animals compared to the control group of animals. Histology indicated that hESC-MSCs survived in considerable numbers and were present in all transplanted animals at 7 weeks leading to solid infilling of the injury site and a reduction in injury site extent compared to the medium injected control group of animals. In conclusion, the results in the first part of the thesis suggest that maximum damage after contusion injury occurs at the time of injury and spontaneous recovery of function largely mitigates the small amount of the secondary damage. Therefore, injury due to high velocity impact might not be amenable to neuroprotective therapies. Furthermore, evidence of modest spontaneous plasticity in the spared corticospinal system suggests some compensatory plasticity after the injuries

Endostatin concentration in plasma of healthy human volunteers

Background: Angiogenesis is involved in many cardiovascular and cancerous diseases, including atherosclerosis and is controlled by a fine balance between angiogenic and angiostatic mediators. Endostatin is one of the main angiostatic mediators, and inhibits angiogenesis and prevents progression of atherosclerosis. The available literature shows a broad range of concentrations in relatively small samples of healthy controls and is calculated by using different techniques. This study was aimed to determine the basal endostatin concentration in plasma of healthy volunteers, to fully understand its physiological role. Methods: Fifty healthy adult volunteers were recruited to the study. Participants were advised not to participate in any physical activity on the day before the blood sampling. The volunteers’ physical activity, height, weight, heart rate and blood pressure were recorded. The samples were analysed for plasma endostatin concentration, using ELISA. The participants were divided by gender and ethnic groups to calculate any difference. Results: Endostatin and other variables were normally distributed. Most of the participants had a moderate level of physical activity with no gender related difference (p=0.370). The mean value for plasma endostatin in all samples was 105±12 ng/ml with range of 81–132 ng/ml. For males, it was 107±13 ng/ml, while for females; 102±12 ng/ml. There were no significant gender or ethnicity related differences in endostatin concentration. Moreover, endostatin was not significantly related with any anthropometric and physical variable. Conclusion: This study gives endostatin levels in normal healthy people and show no gender and ethnicity related differences in endostatin levels. Endostatin was not related with any anthropometric and physical variable

Association of Beta-2 Adrenoreceptor Single Nucleotide Polymorphism with Risk of Type II Diabetes Mellitus

Objective: To determine the genotype of Arg16Gly & Gln27Glu polymorphism in type-2 diabetes mellitus and to find possible association of ADRβ2with type-2 diabetes mellitus. Methodology: A case control study was designed and a total of 192 subjects (98 in each group) were included. After formal approval, subjects were recruited from North West General Hospital (NWGH) Peshawar. After taking consent blood samples were collected from the participants and DNA analysis was done using commercially available kits by salting out protocols, while other biochemical parameters were analyzed using normal laboratory protocols for respective tests. Results: The comparative analysis of SNP rs1042713 indicates that allele G/A was 42(49.4%) in diabetic and 43(50.6%) in non-diabetic subjects. While GG was more frequent 22(59.5%) in diabetic as compare to non-diabetic 15(40.5%). Among AA allele, 19 (65.5%) were non-diabetic while 10(34.5%) were diabetic. However the difference was not statistically significant (p=0.22). In case of “rs1042714” gene the commonest allele was C/C 80 (41.7%) out of which, 47(58.8%) was found in diabetic and 33(41.2%) were non-diabetic. Similarly CG was second common allele out of which diabetics were 27(44.3%) while non-diabetics were 34(55.7%). Allele G/G was found only among 11 subjects (p=0.085). Conclusion: Based on the result of the present study, it is concluded that polymorphism in ADRB2 genes rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu) is associated with susceptibility of T2DM through alteration in BMI & HbA1c

Determination of reference interval (RI) of spot urinary oxalate to creatinine ratio in children of Pakistani origin under six years of age: A cross-sectional study

Background: The gold standard screening method of hyperoxaluria in children is using 24-hour urine collection. Urine collection may be cumbersome and challenging for children. Reference intervals (RI) of oxalate for the Pakistani population are not readily available. Therefore we aimed to determine the oxalate to creatinine ratio (Ox: Cr) for Pakistani children \u3c6 years of age.Materials and methods: A cross-sectional study was conducted at Aga Khan University from June 2018 to October 2019. Random urine samples from apparently healthy children \u3c 6 years were collected and stored at -30°C until analysis after adding 6M HCl. Oxalate was measured on Micro lab 300 using a kit based on oxalate oxidase principle, while creatinine was measured by kinetic Jaffe reaction. Data was analyzed by EP evaluator and SPSS 23. Ox: Cr ratio was calculated and reported with 90% confidence interval (CI) and interquartile range (IQR).Results: The mean age of study subjects (n=120) was 29 ±22.3 months with an M: F ratio of 1:1. Children of various ethnicities were included from all over Karachi. The majority of the subjects were Urdu speaking (37.5%). Median Ox: Cr was 0.13(0.10). No significant difference was noted in the median Ox: Cr ratio between various ethnicities (p\u3e0.05). It was significantly different in group I to V which was 0.25 (IQR: 0.06), 0.19 (IQR: 0.11), 0.15 (IQR: 0.04), 0.11 (IQR: 0.06) and 0.08 (IQR: 0.04) respectively (pvalue \u3c0.001).Conclusion: The established RIs of Ox: Cr ratio was 0.05-0.34 (90% CI). Ox: Cr ratio showed a declining trend with age. Large scale reference interval studies are encouraged, taking diet and age into consideration

Correlation between maternal and neonatal blood Vitamin D level; A cross sectional study of 416 participants visiting a tertiary care hospital in Pakistan

In Pakistan there is limited evidence for the levels and relationship of 25 (OH) Vitamin D [25(OH)D] status in pregnant women and their newborns while the association between maternal 25(OH)D and newborn anthropometric measurements remains unexplored. Sociodemographic data was collected from 213 pregnant mothers during their visit to a tertiary care hospital at the time of childbirth. Anthropometric measurements were performed on all mothers and their newborns and blood samples collected from both for 25(OH)D levels. Participants were classified into two groups according to their 25(OH)D status: Sufficient (25(OH)D ≥50nmol/l) and Deficient (25(OH)D 0.05). Our study shows a high prevalence of 25(OH)D deficiency in pregnant women and their newborns and a strong positive association between maternal and newborn 25(OH)D levels. Findings of this study indicate the importance of maintaining sufficient 25(OH)D levels during pregnancy

Mapping geographical inequalities in access to drinking water and sanitation facilities in low-income and middle-income countries, 2000-17

Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. Methods The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODErn), to generate cause fractions and cause specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. Findings At the broadest grouping of causes of death (Level 1), non-communicable diseases (NC Ds) comprised the greatest fraction of deaths, contributing to 73.4% (95% uncertainty interval [UI] 72.5-74.1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 186% (17.9-19.6), and injuries 8.0% (7.7-8.2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22.7% (21.5-23.9), representing an additional 7.61 million (7. 20-8.01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7.9% (7.08.8). The number of deaths for CMNN causes decreased by 222% (20.0-24.0) and the death rate by 31.8% (30.1-33.3). Total deaths from injuries increased by 2.3% (0-5-4-0) between 2007 and 2017, and the death rate from injuries decreased by 13.7% (12.2-15.1) to 57.9 deaths (55.9-59.2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118.0% (88.8-148.6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36.4% (32.2-40.6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33.6% (31.2-36.1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respirator}, infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990 neonatal disorders, lower respiratory infections, and diarrhoeal diseases were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. Interpretation Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2\ub75th percentile and 100 as the 97\ub75th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59\ub74 (IQR 35\ub74–67\ub73), ranging from a low of 11\ub76 (95% uncertainty interval 9\ub76–14\ub70) to a high of 84\ub79 (83\ub71–86\ub77). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of 'leaving no one behind', it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990-2017, projected indicators to 2030, and analysed global attainment. METHODS: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0-100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator