MiRNAs are essential mediators of many biological processes. The aim of this study was to investigate the dynamics of miRNA-mRNA regulatory networks during exercise and the subsequent recovery period.
Here we monitored the transcriptome changes using microarray analysis of the whole blood of eight highly trained athletes before and after 30 min of moderate exercise followed by 30 min and 60 min of recovery period. We combined expression profiling and bioinformatics and analysed metabolic pathways enriched with differentially expressed mRNAs and mRNAs which are known to be validated targets of differentially expressed miRNAs. Finally we revealed four dynamically regulated networks comprising differentially expressed miRNAs and their known target mRNAs with anti-correlated expression profiles over time. The data suggest that hsa-miR-21-5p regulated TGFBR3, PDGFD and PPM1L mRNAs. Hsa-miR-24-2-5p was likely to be responsible for MYC andKCNJ2 genes and hsa-miR-27a-5p for ST3GAL6. The targets of hsa-miR-181a-5p included ROPN1L and SLC37A3. All these mRNAs are involved in processes highly relevant to exercise response, including immune function, apoptosis, membrane traffic of proteins and transcription regulation.
We have identified metabolic pathways involved in response to exercise and revealed four miRNA-mRNA networks dynamically regulated following exercise. This work is the first study to monitor miRNAs and mRNAs in parallel into the recovery period. The results provide a novel insight into the regulatory role of miRNAs in stress adaptation.
The performance of the three methods depends on the amount of averaged trials. Moreover, differences are found on both amplitude and latency of ERP components recorded in two environments (0 T vs 3 T). We showed that, while ERPs can be extracted from simultaneous EEG–fMRI data at 3 T, the static magnetic field might affect the physiological processes under investigation.The reproducibility of the ERPs in different recording environments (0 T vs 3 T) is a relevant issue that deserves further investigation to clarify the equivalence of cognitive processes in both behavioral and imaging studies.
The processing of sound changes and involuntary attention to them has been widely studied with event-related brain potentials (ERPs). Recently, functional magnetic resonance imaging (fMRI) has been applied to determine the neural mechanisms of involuntary attention and the sources of the corresponding ERP components. The gradient-coil switching noise from the MRI scanner, however, is a challenge to any experimental design using auditory stimuli. In the present study, the effects of MRI noise on ERPs associated with preattentive processing of sound changes and involuntary switching of attention to them were investigated. Auditory stimuli consisted of frequently presented “standard” sounds, infrequent, slightly higher “deviant” sounds, and infrequent natural “novel” sounds. The standard and deviant sounds were either sinusoidal tones or musical chords, in separate stimulus sequences. The mismatch negativity (MMN) ERP associated with preattentive sound change detection was elicited by the deviant and novel sounds and was not affected by the prerecorded background MRI noise (in comparison with the condition with no background noise). The succeeding positive P3a ERP responses associated with involuntary attention switching elicited by novel sounds were also not affected by the MRI noise. However, in ERPs to standard tones and chords, the P1, N1, and P2 peak latencies were significantly prolonged by the MRI noise. Moreover, the amplitude of the subsequent “exogenous” N2 to the standard sounds was significantly attenuated by the presence of MRI noise. In conclusion, the present results suggest that in fMRI the background noise does not interfere with the imaging of auditory processing related to involuntary attention.
To test a novel social network HIV risk-reduction intervention for MSM in Russia and Hungary, where same-sex behavior is stigmatized and men may best be reached through their social network connections.DESIGN:
A two-arm trial with 18 sociocentric networks of MSM randomized to the social network intervention or standard HIV/STD testing/counseling.SETTING:
St. Petersburg, Russia and Budapest, Hungary.PARTICIPANTS:
Eighteen 'seeds' from community venues invited the participation of their MSM friends who, in turn, invited their own MSM friends into the study, a process that continued outward until eighteen three-ring sociocentric networks (mean size = 35 members, n = 626) were recruited.INTERVENTION:
Empirically identified network leaders were trained and guided to convey HIV prevention advice to other network members.MAIN OUTCOME AND MEASURES:
Changes in sexual behavior from baseline to 3-month and 12-month follow-up, with composite HIV/STD incidence, measured at 12 months to corroborate behavior changes.RESULTS:
There were significant reductions between baseline, first follow-up, and second follow-up in the intervention versus comparison arm for proportion of men engaging in any unprotected anal intercourse (UAI) (P = 0.04); UAI with a nonmain partner (P = 0.04); and UAI with multiple partners (P = 0.002). The mean percentage of unprotected anal intercourse acts significantly declined (P = 0.001), as well as the mean number of UAI acts among men who initially had multiple partners (P = 0.05). Biological HIV/STD incidence was 15% in comparison condition networks and 9% in intervention condition networks.CONCLUSION:
Even where same-sex behavior is stigmatized, it is possible to reach MSM and deliver HIV prevention through their social networks.
The effects of functional magnetic resonance imaging (fMRI) acoustic noise were investigated on the parameters of event-related responses (ERPs) elicited during auditory matching-to-sample location and pitch working memory tasks. Stimuli were tones with varying location (left or right) and frequency (high or low). Subjects were instructed to memorize and compare either the locations or frequencies of the stimuli with each other. Tape-recorded fMRI acoustic noise was presented in half of the experimental blocks. The fMRI noise considerably enhanced the P1 component, reduced the amplitude and increased the latency of the N1, shortened the latency of the N2, and enhanced the amplitude of the P3 in both tasks. The N1 amplitude was higher in the location than pitch task in both noise and no-noise blocks, whereas the task-related N1 latency difference was present in the no-noise blocks only. Although the task-related differences between spatial and nonspatial auditory responses were partially preserved in noise, the finding that the acoustic gradient noise accompanying functional MR imaging modulated the auditory ERPs implies that the noise may confound the results of auditory fMRI experiments especially when studying higher cognitive processing
Optimal choice of glucocorticoids (GC), like dexamethasone (DEXA) vs (methyl)prednisolone (MePRED) for remission induction in childhood acute lymphoblastic leukemia (ALL) remains controversial. The favorable antileukemic efficacy of DEXA is off-set by its dose-limiting toxicity. Hence, one objective of trial ALL-Moscow/Berlin (MB) 2002 was to evaluate whether an equiactive dose of MePRED leads to superior event-free survival (EFS) rates by reducing mortality, while maintaining the low relapse rates and central nervous system (CNS) protection obtained with DEXA previously. Of 1163 pediatric patients with newly diagnosed B-cell precursor or T-cell ALL, 1064 were randomized to induction with either 6 mg/m^2 DEXA (n=539) or 60mg/m^2 MePRED(n=525).
Background Timely assessment of HIV/AIDS burden is essential for policy-setting and program evaluation. Based on the Global Burden of Disease study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, ART coverage and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high quality vital registration data, we estimated prevalence and incidence from antenatal clinic data and population-based sero-prevalence surveys and assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates, on and off antiretroviral therapy mortality (ART), and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. Estimation of incidence, prevalence and death uses GBD versions of the EPP and Spectrum software originally developed by UNAIDS. These versions have been recoded for speed and use updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high quality vital registration data, we developed the Cohort Incidence Bias Adjustment model to estimate HIV incidence and prevalence largely from the number of deaths due to HIV recorded in cause of death statistics. Cause of death statistics have been corrected for garbage coding and HIV misclassification. Findings Globally, HIV incidence reached its peak in 1997 at 3.3 million. Annual incidence has stayed relatively constant at about 2.5 million since 2005 after a period of faster decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38.8 million in 2015. At the same time, mortality due to HIV/AIDS has been declining at a steady pace from its peak at 1.8 million deaths in 2005 to 1.2 million deaths in 2015. There is substantial heterogeneity in the levels and trends of HIV/AIDS across countries. While success stories can be found in many countries with improved mortality due to HIV/AIDS and declines in annual new infections, slowdowns or increases in rate of change in annual new infections has been observed elsewhere. Manuscript Interpretation The global scale-up of ART and PMTCT has been one of the great successes of global health in the last two decades. In the last decade, progress reducing new infections has been very slow, development assistance for health devoted to HIV has stagnated, and low-income country resources for health have grown slowly. New ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90- 90 UNAIDS targets will be hard to achieve
Fragmentation in organization and discontinuities in the provision of medical care are problems in all health systems. A major challenge is to strengthen integration in order to enhance efficiciency and health outcomes. This artickle assesses issues related to fragmentation and integration in concptual terms and argues that key attributes of integration are teamwork, coordination and continuity of care. It then presents a summary of service integration problems in Russia and the results of a large survey of physicians concerning the attributes of integration. It is argued that characteristics of the national service delivery model don't ensure integration. Teh Senashko model is not an equivalent to the integrated model. Big organizational forms of service provision, like polyclinics and integrated hospitals-polyclinics don't have higher scores of integration indicators than smaller ones. Proposals to improve integration in Russia are presented with the focus on the regular evaluation of integration/fragmentation, regulation of integration activities, enhancing the role of PHC providers, economic incentives.
A large body of evidence indicates modified expression of protein-coding genes in response to different kinds of physical activity. Recent years have exposed another level of regulation of cellular processes mediated by non-coding RNAs. MicroRNAs (miRNAs) are one of the largest families of non-coding RNAs. MiRNAs mediate post-transcriptional regulation of gene expression. The amount of data supporting the key role of miRNAs in the adaptation of the immune and other body systems to exercise steadily grows. MiRNAs change their expression profiles after exercise and seem to be involved in regulation of exercise-responsive genes in immune and other cell types. Here we discuss existing data and future directions in the field.
A large body of evidence indicates modified expression of protein-coding genes in response to different kinds of physical activity. Recent years have exposed ano- ther level of regulation of cellular processes mediated by non-coding RNAs. MicroRNAs (miRNAs) are one of the largest families of non-coding RNAs. MiR- NAs mediate post-transcriptional regulation of gene expression. The amount of data supporting the key role of miRNAs in the adaptation of the immune and other body systems to exercise steadily grows. MiRNAs change their expression profi- les after exercise and seem to be involved in regulation of exercise-responsive genes in immune and other cell types. Here we discuss existing data and future directions in the field.
How do human brain networks react to dynamic changes in the sensory environment? We measured rapid changes in brain network organization in response to brief, discrete, salient auditory stimuli. We estimated network topology and distance parameters in the immediate central response period, <1 s following auditory presentation of standard tones interspersed with occasional deviant tones in a mismatch-negativity (MMN) paradigm, using magnetoencephalography (MEG) to measure synchronization of high-frequency (gamma band; 33-64 Hz) oscillations in healthy volunteers. We found that global small-world parameters of the networks were conserved between the standard and deviant stimuli. However, surprising or unexpected auditory changes were associated with local changes in clustering of connections between temporal and frontal cortical areas and with increased interlobar, long-distance synchronization during the 120- to 250-ms epoch (coinciding with the MMN-evoked response). Network analysis of human MEG data can resolve fast local topological reconfiguration and more long-range synchronization of high-frequency networks as a systems-level representation of the brain's immediate response to salient stimuli in the dynamically changing sensory environment.
Status epilepticus (SE) provokes changes, which lead to neuronal alterations. Endocannabinoids (eCBs) can affect the neuronal survival during excitotoxicity and brain damage. Using a kainic acid (KA)-induced experimental SE model, we investigated whether cellular changes entail damage to endoplasmic reticulum (ER), mitochondria, and nuclei in hippocampal cells (CA1 field), and whether these alterations can be diminished by treatment with URB597, an inhibitor of eCB enzymatic degradation.
Material and methods
SE was induced in Wistar rats by the microinjection of KA into the lateral ventricle. URB597 or a vehicle (10% DMSO) were injected in the same way into the brain of animals 24 h after the KA infusion and then daily for the next nine days. The behavior of animals was controlled visually and recorded with a video system. The intensity of SE significantly varied in different animals. Convulsive (stages 3–5 according to the Racine scale) and nonconvulsive seizures (mainly stages 1, 2 and rarely 3, 4) were recognized.
Two weeks after SE, a significant loss of hippocampal cells occurred in animals with KA injections. In survived cells, ultrastructural alterations in ER, mitochondria, and nuclei of hippocampal neurons were observed. The degree of cell injury depended on the severity of SE. Alterations evoked by moderate seizures were prevented or diminished by URB597, but strong seizures induced mostly irreversible damage.
The beneficial impact of the FAAH inhibitor URB597 can give impetus to the development of novel neuroprotective strategies.
This study investigates whether economic freedom of a region drives firm performance. Despite the large number of papers about the relationship between economic freedom and growth, there is still little evidence on the role of economic freedom in performance of individual firms. We address this gap in the literature using hierarchical linear modelling, allowing us to investigate regional differences in company level performance. The dataset consists of information about 1096 companies combined with the Index of Economic Freedom for Russian regions during the period 2004 – 2014
The paper deals with the Forrester’s approach to analysis of heart electrical dynamics based on the hypothesis that heart belongs to the class of Complex Systems and its dynamics can be described by coupled Van der Pol differential equations with a time lag. The chain of such equations suggested by Ginzburg and Landau was used to describe such states of heart dynamics as normal beatings, fibrillation and ischemia through the kinds of the chain dynamics as regular oscillations, chaotic dynamics and intermittency dynamics of order – disorder type correspondingly. The mathematical model supporting the hypothesis demonstrated all mentioned model modes of heart functioning. During the computer, study of the model another hypothesis has been put forward concerning the existence in the heart dynamics a special oscillatory region, which interacts with ischemia oscillatory region lowering its energy. According to the prediction, both regions had to have different resonant parameters. Taking into account the results of the model study there has been made another prediction about possible synchronization of the heartbeats by applying external periodical perturbation at frequency of about 1 Hz. The pilot data supporting the proposed hypothesis have demonstrated the reality of the suggested hypothesis. In particular, the real ECG and their Fourier spectra of healthy patients corresponded to the model regular ECG and their Fourier spectra. The ECG Fourier spectrum of the patient with a cardio stimulator corresponded to the model synchronization of the ECG and its Fourier spectrum generated by the developed mathematical model. As far as the ECGs and Fourier spectra in patients with differently developed ischemia are concerned, they confirmed the hypothesis about the existing of two interacting oscillatory regions in myocardium: the ischemic and the defending ones. The defending region decreases the volume of the ischemic process through lowering its energy. Summing it up one can conclude that the experimental results confirmed the suggested hypothesis and the prediction following from it.
The present study systematically compared the neural and behavioral accuracy of discriminating a frequency change (“deviant”) in a repetitive tone (“standard”) across a frequency range of 250–4000 Hz. The sound structure (pure sinusoidal vs. harmonically rich tones) and the magnitude of frequency change (2.5%, 5%, 10%, 20%) were also varied. The accuracy of neural frequency-change detector was determined by comparing the auditory event-related potentials (ERP) elicited by deviant and standard stimuli in the absence of attention. In a separate behavioral task, subjects were to indicate when they noticed a frequency change. The ranges of the across-subject means of ERP parameters across the conditions were: the mismatch negativity (MMN) amplitude −0.9 to −4.9 μV, latency 125–218 ms, the P3a amplitude 0.3–3.2 μV, latency 239–304 ms. The ERP latency was shortest for the standard-stimulus frequency from 1000 to 2000 Hz suggesting that automatic frequency discrimination was the most accurate in that range. The ERP latencies and amplitudes correlated with the hit rate (HR) and reaction time (RT), with highest correlation found between the MMN amplitude and the HR (r=0.8). The harmonical tones elicited MMN and P3a with shorter latencies and larger amplitudes, than did pure sinusoidal tones in all frequency bands. The results may have implication to pitch-perception theories
The loud acoustic noise produced by the magnetic resonance scanner is a major source of interference in auditory fMRI research. Whole-head magnetoencephalography (MEG) was used to investigate the interaction between the frequency range of auditory stimulation and fMRI acoustic noise. Pure tones and 3-harmonic complexes varying between 240 and 1240 Hz in frequency were presented while participants attended to a silent subtitled film. Continuous fMRI acoustic noise was presented during half of the blocks. The activity in six regions of interest was analyzed in 100–200 and 200–300 ms time windows to evaluate the magnetic counterparts of the mismatch negativity (MMN) and P3a brain responses. The results suggested that fMRI noise significantly reduced the amplitude of these responses. The effect of the noise on the automatic processing of the tones was more prominent for the tones with frequencies higher than 500 Hz. It is recommended that in the MMN protocols using continuous fMRI acquisition the sound stimuli should be spectrally separated from the fMRI scanner noise spectrum.
In Parkinson's disease (PD) levodopa-associated changes in the power and long-range temporal correlations of beta oscillations have been demonstrated, yet the presence and modulation of genuine connectivity in local field potentials (LFP) recorded from the subthalamic nucleus (STN) remains an open question. The present study investigated LFP recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and after a single dose levodopa administration (ON). We utilized connectivity measures being insensitive to volume conduction (functional connectivity: non-zero imaginary part of coherency; effective connectivity: phase-slope index). We demonstrated the presence of neuronal interactions in the frequency range of 10-30 Hz in STN-LFP without a preferential directionality of interactions between different contacts along the electrode tracks. While the direction of neuronal interactions per se was preserved after levodopa administration, functional connectivity and the ventral-dorsal information flow were modulated by medication. The OFF-ON differences in functional connectivity were correlated with the levodopa-induced improvement in clinical Unified Parkinson's Disease Rating Scale scores. We hypothesize that regional neuronal interactions, as reflected in STN-LFP connectivity, might represent a basis for the intra-nuclear spatial specificity of deep brain stimulation. Moreover, our results suggest the potential use of volume conduction-insensitive measures of connectivity in STN-LFP as a marker of clinical motor symptoms in PD.
Background Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65·3 years (UI 65·0–65·6) in 1990, to 71·5 years (UI 71·0–71·9) in 2013, while the number of deaths increased from 47·5 million (UI 46·8–48·2) to 54·9 million (UI 53·6–56·3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25–39 years and older than 75 years and for men aged 20–49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10·7%, from 4·3 million deaths in 1990 to 4·8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.
Calcium plays a role of universal cellular regulator in the living cell and one of the crucial regulators of proper fetal development during gestation. Mitochondria are important for intracellular calcium handling and signaling. Mitochondrial calcium uniporter (mtCU) is a multiprotein complex of the mitochondrial inner membrane responsible for the transport of calcium to the mitochondrial matrix. In the present study, we analyzed the expression level of mtCU components in two parts of the feto-maternal system - placenta and myometrium at full-term delivery and at preterm birth (PTB) on different stages: 22-27, 28-32, 33-36 weeks of gestation (n = 50). A gradual increase of mRNA expression and changes in protein content of MCU and MICU1 subunits were revealed in the placenta during gestation. We also observed slower depolarization rate of isolated placental mitochondria induced by Ca2+ titration at PTB. In myometrium at PTB relative gene expression level of MCU, MCUb and SMDT1 increased as compared to full-term pregnancy, but the tendency to gradual increase of MCU protein simultaneous with MCUb increase and MICU1 decline was shown in gestational dynamics. Changes observed in the present study might be considered both natural dynamics as well as possible pathological mechanisms underlying preterm birth.
Importance The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce.
Objective To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study.
Evidence Review Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14 244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35 620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates.
Findings Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905 059 deaths; 95% UI, 810 304-998 125), diarrheal diseases among older children (38 325 deaths; 95% UI, 30 365-47 678), and road injuries among adolescents (115 186 deaths; 95% UI, 105 185-124 870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world’s deaths from neonatal encephalopathy. Half of the world’s diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia.
Conclusions and Relevance Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.