Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Zoledronic acid targets chemo-resistant polyploid giant cancer cells

Abstract Although polyploid giant cancer cells (PGCCs) are known as a key source of failure of current therapies, sufficient drugs to target these cells are not yet introduced. Considering the similarities of polyploid cells in regeneration and cancer, we hypothesized that zoledronic acid (ZA), an osteoclast-targeting agent, might be used to eliminate PGCCs. The 5637-bladder cancer cell line was treated with various doses of cisplatin to enrich polyploid cells and the efficacy of different concentrations of ZA in reducing this population was assessed. The metabolic profile of PGCCs was investigated with gas chromatography-mass spectrometry. Lipid profiles, mitochondrial density, and ROS content were also measured to assess the response of the cells to ZA. Cancer cells surviving after three days of exposure with 6 μM cisplatin were mainly polyploid. These cells demonstrated special morphological features such as fusion with diploid or other polyploid cells and originated in daughter cells through budding. ZA could substantially eradicate PGCCs with the maximal effect observed with 50 μM which resulted in the drop of PGCC fraction from 60 ± 7.5 to 19 ± 1.7%. Enriched PGCCs after cisplatin-treatment demonstrated a drastic metabolic shift compared to untreated cancer cells with an augmentation of lipids. Further assays confirmed the high content of lipid droplets and cholesterol in these cells which were reduced after ZA administration. Additionally, the mitochondrial density and ROS increased in PGCCs both of which declined in response to ZA. Taken together, we propose that ZA is a potent inhibitor of PGCCs which alters the metabolism of PGCCs. Although this drug has been successfully exploited as adjuvant therapy for some malignancies, the current evidence on its effects on PGCCs justifies further trials to assess its potency for improving the success of current therapies for tackling tumor resistance and relapse

Colored petri net modeling of small interfering RNA-mediated messenger RNA degradation

Background: Mathematical modeling of biological systems is an attractive way for studying complex biological systems and their behaviors. Petri Nets, due to their ability to model systems with various levels of qualitative information, have been wildly used in modeling biological systems in which enough qualitative data may not be at disposal. These nets have been used to answer questions regarding the dynamics of different cell behaviors including the translation process. In one stage of the translation process, the RNA sequence may be degraded. In the process of degradation of RNA sequence, small-noncoding RNA molecules known as small interfering RNA (siRNA) match the target RNA sequence. As a result of this matching, the target RNA sequence is destroyed. Materials and Methods: In this context, the process of matching and destruction is modeled using Colored Petri Nets (CPNs). The model is constructed using CPNs which allow tokens to have a value or type on them. Thus, CPN is a suitable tool to model string structures in which each element of the string has a different type. Using CPNs, long RNA, and siRNA strings are modeled with a finite set of colors. The model is simulated via CPN Tools. Results: A CPN model of the matching between RNA and siRNA strings is constructed in CPN Tools environment. Conclusion: In previous studies, a network of stoichiometric equations was modeled. However, in this particular study, we modeled the mechanism behind the silencing process. Modeling this kind of mechanisms provides us with a tool to examine the effects of different factors such as mutation or drugs on the process

The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach.

Fibroblasts as key components of tumor microenvironment show different features in the interaction with cancer cells. Although, Normal fibroblasts demonstrate anti-tumor effects, cancer associated fibroblasts are principal participant in tumor growth and invasion. The ambiguity of fibroblasts function can be regarded as two heads of its behavioral spectrum and can be subjected for mathematical modeling to identify their switching behavior. In this research, an agent-based model of mutual interactions between fibroblast and cancer cell was created. The proposed model is based on nonlinear differential equations which describes biochemical reactions of the main factors involved in fibroblasts and cancer cells communication. Also, most of the model parameters are estimated using hybrid unscented Kalman filter. The interactions between two cell types are illustrated by the dynamic modeling of TGFβ and LIF pathways as well as their crosstalk. Using analytical and computational approaches, reciprocal effects of cancer cells and fibroblasts are constructed and the role of signaling molecules in tumor progression or prevention are determined. Finally, the model is validated using a set of experimental data. The proposed dynamic modeling might be useful for designing more efficient therapies in cancer metastasis treatment and prevention

SALL4: An Intriguing Therapeutic Target in Cancer Treatment

Spalt-Like Transcription Factor 4 (SALL4) is a critical factor for self-renewal ability and pluripotency of stem cells. On the other hand, various reports show tight relation of SALL4 to cancer occurrence and metastasis. SALL4 exerts its effects not only by inducing gene expression but also repressing a large cluster of genes through interaction with various epigenetic modifiers. Due to high expression of SALL4 in cancer cells and its silence in almost all adult tissues, it is an ideal target for cancer therapy. However, targeting SALL4 meets various challenges. SALL4 is a transcription factor and designing appropriate drug to inhibit this intra-nucleus component is challenging. On the other hand, due to lack of our knowledge on structure of the protein and the suitable active sites, it becomes more difficult to reach the appropriate drugs against SALL4. In this review, we have focused on approaches applied yet to target this oncogene and discuss the potential of degrader systems as new therapeutics to target oncogenes

Galaxy Sizes Since z=2 from the Perspective of Stellar Mass Distribution within Galaxies

How stellar mass assembles within galaxies is still an open question. We present measurements of the stellar mass distribution on kiloparsec-scales for similar to 5500 galaxies with stellar masses above log(M*/M-circle dot) >= 9.8 up to redshift 2.0. We create stellar mass maps from Hubble Space Telescope observations by means of the pixel-by-pixel spectral energy distribution fitting method. These maps are used to derive radii encompassing 20%, 50%, and 80% (r(20), r(50), and r(80)) of the total stellar mass from the best-fit Sersic models. The reliability and limitations of the structural parameter measurements are checked extensively using a large sample (similar to 3000) of simulated galaxies. The size-mass relations and redshift evolution of r(20), r(50), and r(80) are explored for star-forming and quiescent galaxies. At fixed mass, the star-forming galaxies do not show significant changes in their r(20), r(50), and r(80) sizes, indicating self-similar growth. Only above the pivot stellar mass of log(M*/M-circle dot) similar or equal to 10.5 does r(80) evolve as r(80) proportional to (1 + z)(-0.85 +/- 0.20), indicating that mass builds up in the outskirts of these systems (inside-out growth). The Sersic values also increase for the massive star-forming galaxies toward late cosmic time. Massive quiescent galaxies show stronger size evolution at all radii, in particular, the r(20) sizes. For these massive galaxies, Sersic values remain almost constant since at least z similar to 1.3, indicating that the strong size evolution is related to the changes in the outer parts of these galaxies. We make all the structural parameters publicly available

Identification of Appropriate Housekeeping Genes for Gene Expression Analysis in Long-term Hypoxia-treated Kidney Cells

Background: Selection of stably expressing housekeeping genes (HKGs) is a crucial step in gene expression analysis. However, there are no universal HKGs for all experiments, and they should be determined by each biologic condition. The aim of this study was to detect appropriate HKGs for kidney cells cultured in long-term hypoxia. Materials and Methods: Based on a screening step using a microarray data available from gene expression omnibus database, a set of candidate HKGs were chosen to be assessed in human kidney cells cultured in hypoxic or normoxic conditions for about 2 weeks in a time course manner. The stability of gene expression was assessed by refFinder, a web-based tool that integrates four computational programs (geNorm, Normfinder, BestKeeper, and the comparative ΔΔCt method). Results: GAPDH and ACTB were the most stable genes in hypoxia treated cells whereas, B2M and ACTB were the best HKGs in cells cultured in normoxia. When both hypoxia and normoxia treated cells from all time points were evaluated together, GAPDH and ACTB equally showed the most stability. Conclusion: As in relative quantification of real-time polymerase chain reaction data, the same HKGs should be selected for all groups, we believe that GAPDH and ACTB are suitable HKGs for studies on the effect of hypoxia on cultured kidney cells

Dental Treatment Needs in Thalassemia Major Patients, Sari, Iran

Background and purpose: Patients with thalassemia major need more dental care because of their special health conditions. The purpose of this study was to evaluate dental health and therapeutic needs of these patients in Sari, Iran 2018. Materials and methods: A descriptive cross-sectional study was done using a researcher-made form and direct observation in 144 cases attending Sari Thalassemia Center. The subjects included thalassemia patients (41 males and 34 females) and 69 individuals as the control group. The needs for dental treatment and prevalence of dental problems were recorded using Decayed, Missing, and Filled Teeth (DMFT) index. Data analysis was done in SPSS V24. Results: There were significant differences between the two groups in DMFT index (P< 0.001), decayed teeth (P= 0.004), and missing teeth (P=0.001). In fact, the values except the mean number of filled teeth were higher in thalassemia patients (P=0.150). Pulp therapy was the most common treatment needed in thalassemia patients while dental filling was more needed in control group. Conclusion: High prevalence of dental caries in patients with thalassemia major highlights the need for effective preventive measures, appropriate health trainings, and dental treatments in this group

Dietary Antioxidant Capacity Indices are Negatively Correlated to LDL-Oxidation in Adults

Introduction. Former research studies have demonstrated controversial associations between dietary indices and oxidative stress biomarkers including oxidized low-density lipoprotein (ox-LDL) and malondialdehyde (MDA). So, in this cross-sectional study, we aimed to assess the association of dietary total antioxidant capacity (DTAC), oxidative balance score, and phytochemical index (PI) with ox-LDL/MDA in a healthy adult population of Shiraz, Iran. Methods. 236 individuals participated in this cross-sectional study. DTAC, OBS, and PI were calculated using a 168-item food frequency questionnaire (FFQ), which was previously validated in Iran. We measured ox-LDL and MDA in blood samples of the participants using commercially existing kits. Crude and adjusted models of linear regression were used to evaluate the relation of dietary indices with ox-LDL and MDA. Results. There was a significant association between ox-LDL and DTAC in both crude (β = −1.55; 95% CI: −2.53, −0.58; P-trend = 0.002) and adjusted (β = −1.65 95% CI: −2.66, −0.64; P-trend = 0.001) models. Also, a negative association was observed between ox-LDL and PI in the crude (β = −1.26 95% CI: −2.33, −0.29; P-trend = 0.01) and adjusted (β = −1.36 95% CI: −2.38, −0.34; P-trend = 0.01) models. Conclusion. Results of this study showed that DTAC and PI were inversely associated with ox-LDL as markers of lipid peroxidation. But no correlations were seen between MDA and dietary antioxidant indices