The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern. The development of vaccines with high ...immunogenicity and safety is crucial for controlling the global COVID-19 pandemic and preventing further illness and fatalities. Here, we report the development of a SARS-CoV-2 vaccine candidate, Nanocovax, based on recombinant protein production of the extracellular (soluble) portion of the spike (S) protein of SARS-CoV-2. The results showed that Nanocovax induced high levels of S protein-specific IgG and neutralizing antibodies in three animal models: BALB/c mouse, Syrian hamster, and a non-human primate (
). In addition, a viral challenge study using the hamster model showed that Nanocovax protected the upper respiratory tract from SARS-CoV-2 infection. Nanocovax did not induce any adverse effects in mice (
var. albino) and rats (
). These preclinical results indicate that Nanocovax is safe and effective.
CD8
T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8
T cell immunity directed at the prominent influenza ...epitope HLA-A*02:01-M1
(A2/M1
) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M1
CD8
T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8
T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8
T cell responses toward viral infections.
Previous congenital heart disease estimates came from few data sources, were geographically narrow, and did not evaluate congenital heart disease throughout the life course. Completed as part of the ...Global Burden of Diseases, Injuries, and Risk Factors Study 2017, this study aimed to provide comprehensive estimates of congenital heart disease mortality, prevalence, and disability by age for 195 countries and territories from 1990 to 2017.
Mortality estimates were generated for aggregate congenital heart disease and non-fatal estimates for five subcategories (single ventricle and single ventricle pathway congenital heart anomalies; severe congenital heart anomalies excluding single ventricle heart defects; critical malformations of great vessels, congenital valvular heart disease, and patent ductus arteriosus; ventricular septal defect and atrial septal defect; and other congenital heart anomalies), for 1990 through to 2017. All available global data were systematically analysed to generate congenital heart disease mortality estimates (using Cause of Death Ensemble modelling) and prevalence estimates (DisMod-MR 2·1). Systematic literature reviews of all types of congenital anomalies to capture information on prevalence, associated mortality, and long-term health outcomes on congenital heart disease informed subsequent disability estimates.
Congenital heart disease caused 261 247 deaths (95% uncertainty interval 216 567–308 159) globally in 2017, a 34·5% decline from 1990, with 180 624 deaths (146 825–214 178) being among infants (aged <1 years). Congenital heart disease mortality rates declined with increasing Socio-demographic Index (SDI); most deaths occurred in countries in the low and low-middle SDI quintiles. The prevalence rates of congenital heart disease at birth changed little temporally or by SDI, resulting in 11 998 283 (10 958 658–13 123 888) people living with congenital heart disease globally, an 18·7% increase from 1990 to 2017, and causing a total of 589 479 (287 200–973 359) years lived with disability.
Congenital heart disease is a large, rapidly emerging global problem in child health. Without the ability to substantially alter the prevalence of congenital heart disease, interventions and resources must be used to improve survival and quality of life. Our findings highlight the large global inequities in congenital heart disease and can serve as a starting point for policy changes to improve screening, treatment, and data collection.
Bill & Melinda Gates Foundation.
Through the Global Burden of Diseases, Injuries, and Risk Factors (GBD) studies, headache has emerged as a major global public health concern. We aimed to use data from the GBD 2016 study to provide ...new estimates for prevalence and years of life lived with disability (YLDs) for migraine and tension-type headache and to present the methods and results in an accessible way for clinicians and researchers of headache disorders.
Data were derived from population-based cross-sectional surveys on migraine and tension-type headache. Prevalence for each sex and 5-year age group interval (ie, age 5 years to ≥95 years) at different time points from 1990 and 2016 in all countries and GBD regions were estimated using a Bayesian meta-regression model. Disease burden measured in YLDs was calculated from prevalence and average time spent with headache multiplied by disability weights (a measure of the relative severity of the disabling consequence of a disease). The burden stemming from medication overuse headache, which was included in earlier iterations of GBD as a separate cause, was subsumed as a sequela of either migraine or tension-type headache. Because no deaths were assigned to headaches as the underlying cause, YLDs equate to disability-adjusted life-years (DALYs). We also analysed results on the basis of the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility.
Almost three billion individuals were estimated to have a migraine or tension-type headache in 2016: 1·89 billion (95% uncertainty interval UI 1·71–2·10) with tension-type headache and 1·04 billion (95% UI 1·00–1·09) with migraine. However, because migraine had a much higher disability weight than tension-type headache, migraine caused 45·1 million (95% UI 29·0–62·8) and tension-type headache only 7·2 million (95% UI 4·6–10·5) YLDs globally in 2016. The headaches were most burdensome in women between ages 15 and 49 years, with migraine causing 20·3 million (95% UI 12·9–28·5) and tension-type headache 2·9 million (95% UI 1·8–4·2) YLDs in 2016, which was 11·2% of all YLDs in this age group and sex. Age-standardised DALYs for each headache type showed a small increase as SDI increased.
Although current estimates are based on limited data, our study shows that headache disorders, and migraine in particular, are important causes of disability worldwide, and deserve greater attention in health policy debates and research resource allocation. Future iterations of this study, based on sources from additional countries and with less methodological heterogeneity, should help to provide stronger evidence of the need for action.
Bill & Melinda Gates Foundation.
•We propose an automatic method based on liver detection and liver movement estimation for delineating scan range in multiphase CT imaging of liver cancer patients within a second with high accuracy ...compared to the best of state-of-the-art methods.•The study was carried out on 657 multiphase 3D CT images from several hospitals in various countries with two different liver cancer intervention applications.•The proposed method can significantly reduce the effect radiation dose inducting to the patients with a mount of 14.5% (2.56 mSv) on average.•Three radiologists from two hospitals assessed both the range-reduced CT images and the original images and independently concluded that no difference is found in their clinical decision-makings when using either of those images.
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Multiphase CT scanning of the liver is performed for several clinical applications; however, radiation exposure from CT scanning poses a nontrivial cancer risk to the patients. The radiation dose may be reduced by determining the scan range of the subsequent scans by the location of the target of interest in the first scan phase. The purpose of this study is to present and assess an automatic method for determining the scan range for multiphase CT scans. Our strategy is to first apply a CNN-based method for detecting the liver in 2D slices, and to use a liver range search algorithm for detecting the liver range in the scout volume. The target liver scan range for subsequent scans can be obtained by adding safety margins achieved from Gaussian liver motion models to the scan range determined from the scout. Experiments were performed on 657 multiphase CT volumes obtained from multiple hospitals. The experiment shows that the proposed liver detection method can detect the liver in 223 out of a total of 224 3D volumes on average within one second, with mean intersection of union, wall distance and centroid distance of 85.5%, 5.7 mm and 9.7 mm, respectively. In addition, the performance of the proposed liver detection method is comparable to the best of the state-of-the-art 3D liver detectors in the liver detection accuracy while it requires less processing time. Furthermore, we apply the liver scan range generation method on the liver CT images acquired from radiofrequency ablation and Y-90 transarterial radioembolization (selective internal radiation therapy) interventions of 46 patients from two hospitals. The result shows that the automatic scan range generation can significantly reduce the effective radiation dose by an average of 14.5% (2.56 mSv) compared to manual performance by the radiographer from Y-90 transarterial radioembolization, while no statistically significant difference in performance was found with the CT images from intra RFA intervention (p = 0.81). Finally, three radiologists assess both the original and the range-reduced images for evaluating the effect of the range reduction method on their clinical decisions. We conclude that the automatic liver scan range generation method is able to reduce excess radiation compared to the manual performance with a high accuracy and without penalizing the clinical decision.
Brain and CNS cancers (collectively referred to as CNS cancers) are a source of mortality and morbidity for which diagnosis and treatment require extensive resource allocation and sophisticated ...diagnostic and therapeutic technology. Previous epidemiological studies are limited to specific geographical regions or time periods, making them difficult to compare on a global scale. In this analysis, we aimed to provide a comparable and comprehensive estimation of the global burden of brain cancer between 1990 and 2016.
We report means and 95% uncertainty intervals (UIs) for incidence, mortality, and disability-adjusted life-years (DALYs) estimates for CNS cancers (according to the International Classification of Diseases tenth revision: malignant neoplasm of meninges, malignant neoplasm of brain, and malignant neoplasm of spinal cord, cranial nerves, and other parts of CNS) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. Data sources include vital registration and cancer registry data. Mortality was modelled using an ensemble model approach. Incidence was estimated by dividing the final mortality estimates by mortality to incidence ratios. DALYs were estimated by summing years of life lost and years lived with disability. Locations were grouped into quintiles based on the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate.
In 2016, there were 330 000 (95% UI 299 000 to 349 000) incident cases of CNS cancer and 227 000 (205 000 to 241 000) deaths globally, and age-standardised incidence rates of CNS cancer increased globally by 17·3% (95% UI 11·4 to 26·9) between 1990 and 2016 (2016 age-standardised incidence rate 4·63 per 100 000 person-years 4·17 to 4·90). The highest age-standardised incidence rate was in the highest quintile of SDI (6·91 5·71 to 7·53). Age-standardised incidence rates increased with each SDI quintile. East Asia was the region with the most incident cases of CNS cancer for both sexes in 2016 (108 000 95% UI 98 000 to 122 000), followed by western Europe (49 000 37 000 to 54 000), and south Asia (31 000 29 000 to 37 000). The top three countries with the highest number of incident cases were China, the USA, and India. CNS cancer was responsible for 7·7 million (95% UI 6·9 to 8·3) DALYs globally, a non-significant change in age-standardised DALY rate of −10·0% (−16·4 to 2·6) between 1990 and 2016. The age-standardised DALY rate decreased in the high SDI quintile (−10·0% –27·1 to −0·1) and high-middle SDI quintile (−10·5% –18·4 to −1·4) over time but increased in the low SDI quintile (22·5% 11·2 to 50·5).
CNS cancer is responsible for substantial morbidity and mortality worldwide, and incidence increased between 1990 and 2016. Significant geographical and regional variation in the incidence of CNS cancer might be reflective of differences in diagnoses and reporting practices or unknown environmental and genetic risk factors. Future efforts are needed to analyse CNS cancer burden by subtype.
Bill & Melinda Gates Foundation.
Snakebite envenoming is an important cause of preventable death. The World Health Organization (WHO) set a goal to halve snakebite mortality by 2030. We used verbal autopsy and vital registration ...data to model the proportion of venomous animal deaths due to snakes by location, age, year, and sex, and applied these proportions to venomous animal contact mortality estimates from the Global Burden of Disease 2019 study. In 2019, 63,400 people (95% uncertainty interval 38,900-78,600) died globally from snakebites, which was equal to an age-standardized mortality rate (ASMR) of 0.8 deaths (0.5-1.0) per 100,000 and represents a 36% (2-49) decrease in ASMR since 1990. India had the greatest number of deaths in 2019, equal to an ASMR of 4.0 per 100,000 (2.3-5.0). We forecast mortality will continue to decline, but not sufficiently to meet WHO's goals. Improved data collection should be prioritized to help target interventions, improve burden estimation, and monitor progress.
Zanubrutinib‐treated and treatment‐naïve patients with chronic lymphocytic leukaemia (CLL) or Waldenstrom's macroglobulinaemia were recruited in this prospective study to comprehensively profile ...humoral and cellular immune responses to COVID‐19 vaccination. Overall, 45 patients (median 72 years old) were recruited; the majority were male (71%), had CLL (76%) and were on zanubrutinib (78%). Seroconversion rates were 65% and 77% following two and three doses, respectively. CD4+ and CD8+ T‐cell response rates increased with third dose. In zanubrutinib‐treated patients, 86% developed either a humoral or cellular response. Patients on zanubrutinib developed substantial immune responses following two COVID‐19 vaccine doses, which further improved following a third dose.
Gastro-oesophageal reflux disease is a common chronic ailment that causes uncomfortable symptoms and increases the risk of oesophageal adenocarcinoma. We aimed to report the burden of ...gastro-oesophageal reflux disease in 195 countries and territories between 1990 and 2017, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017.
We did a systematic review to identify measurements of the prevalence of gastro-oesophageal reflux disease in geographically defined populations worldwide between 1990 and 2017. These estimates were analysed with DisMod-MR, a Bayesian mixed-effects meta-regression tool that incorporates predictive covariates and adjustments for differences in study design in a geographical cascade of models. Fitted values for broader geographical units inform prior distributions for finer geographical units. Prevalence was estimated for 195 countries and territories. Reports of the frequency and severity of symptoms among individuals with gastro-oesophageal reflux disease were used to estimate the prevalence of cases with no, mild to moderate, or severe to very severe symptoms at a given time; these estimates were multiplied by disability weights to estimate years lived with disability (YLD).
Data to estimate gastro-oesophageal reflux disease burden were scant, totalling 144 location-years (unique measurements from a year and location, regardless of whether a study reported them alongside measurements for other locations or years) of prevalence data. These came from six (86%) of seven GBD super-regions, 11 (52%) of 21 GBD regions, and 39 (20%) of 195 countries and territories. Mean estimates of age-standardised prevalence for all locations in 2017 ranged from 4408 cases per 100 000 population to 14 035 cases per 100 000 population. Age-standardised prevalence was highest (>11 000 cases per 100 000 population) in the USA, Italy, Greece, New Zealand, and several countries in Latin America and the Caribbean, north Africa and the Middle East, and eastern Europe; it was lowest (<7000 cases per 100 000 population) in the high-income Asia Pacific, east Asia, Iceland, France, Denmark, and Switzerland. Global prevalence peaked at ages 75–79 years, at 18 820 (95% uncertainty interval 95% UI 13 770–24 000) cases per 100 000 population. Global age-standardised prevalence was stable between 1990 and 2017 (8791 95% UI 7772–9834 cases per 100 000 population in 1990 and 8819 7781–9863 cases per 100 000 population in 2017, percentage change 0·3% –0·3 to 0·9), but all-age prevalence increased by 18·1% (15·6–20·4) between 1990 and 2017, from 7859 (6905–8851) cases per 100 000 population in 1990 to 9283 (8189–10 400) cases per 100 000 population in 2017. YLDs increased by 67·1% (95% UI 63·5–70·3) between 1990 and 2017, from 3·60 million (1·93–6·12) in 1990 to 6·01 million (3·22–10·19) in 2017.
Gastro-oesophageal reflux disease is common worldwide, although less so in much of eastern Asia. The stability of our global age-standardised prevalence estimates over time suggests that the epidemiology of the disease has not changed, but the estimates of all-age prevalence and YLDs, which increased between 1990 and 2017, suggest that the burden of gastro-oesophageal reflux disease is nonetheless increasing as a result of ageing and population growth.
Bill & Melinda Gates Foundation.
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