Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases. © 2013 Ziraldo et al

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.Funding/Support: The Institute for Health Metrics and Evaluation received funding from the Bill & Melinda Gates Foundation and the American Lebanese Syrian Associated Charities. Dr Aljunid acknowledges the Department of Health Policy and Management of Kuwait University and the International Centre for Casemix and Clinical Coding, National University of Malaysia for the approval and support to participate in this research project. Dr Bhaskar acknowledges institutional support from the NSW Ministry of Health and NSW Health Pathology. Dr Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, which is funded by the German Federal Ministry of Education and Research. Dr Braithwaite acknowledges funding from the National Institutes of Health/ National Cancer Institute. Dr Conde acknowledges financial support from the European Research Council ERC Starting Grant agreement No 848325. Dr Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia, IP under the Norma Transitória grant DL57/2016/CP1334/CT0006. Dr Ghith acknowledges support from a grant from Novo Nordisk Foundation (NNF16OC0021856). Dr Glasbey is supported by a National Institute of Health Research Doctoral Research Fellowship. Dr Vivek Kumar Gupta acknowledges funding support from National Health and Medical Research Council Australia. Dr Haque thanks Jazan University, Saudi Arabia for providing access to the Saudi Digital Library for this research study. Drs Herteliu, Pana, and Ausloos are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. Dr Hugo received support from the Higher Education Improvement Coordination of the Brazilian Ministry of Education for a sabbatical period at the Institute for Health Metrics and Evaluation, between September 2019 and August 2020. Dr Sheikh Mohammed Shariful Islam acknowledges funding by a National Heart Foundation of Australia Fellowship and National Health and Medical Research Council Emerging Leadership Fellowship. Dr Jakovljevic acknowledges support through grant OI 175014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. Dr Katikireddi acknowledges funding from a NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). Dr Md Nuruzzaman Khan acknowledges the support of Jatiya Kabi Kazi Nazrul Islam University, Bangladesh. Dr Yun Jin Kim was supported by the Research Management Centre, Xiamen University Malaysia (XMUMRF/2020-C6/ITCM/0004). Dr Koulmane Laxminarayana acknowledges institutional support from Manipal Academy of Higher Education. Dr Landires is a member of the Sistema Nacional de Investigación, which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación. Dr Loureiro was supported by national funds through Fundação para a Ciência e Tecnologia under the Scientific Employment Stimulus–Institutional Call (CEECINST/00049/2018). Dr Molokhia is supported by the National Institute for Health Research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. Dr Moosavi appreciates NIGEB's support. Dr Pati acknowledges support from the SIAN Institute, Association for Biodiversity Conservation & Research. Dr Rakovac acknowledges a grant from the government of the Russian Federation in the context of World Health Organization Noncommunicable Diseases Office. Dr Samy was supported by a fellowship from the Egyptian Fulbright Mission Program. Dr Sheikh acknowledges support from Health Data Research UK. Drs Adithi Shetty and Unnikrishnan acknowledge support given by Kasturba Medical College, Mangalore, Manipal Academy of Higher Education. Dr Pavanchand H. Shetty acknowledges Manipal Academy of Higher Education for their research support. Dr Diego Augusto Santos Silva was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil Finance Code 001 and is supported in part by CNPq (302028/2018-8). Dr Zhu acknowledges the Cancer Prevention and Research Institute of Texas grant RP210042

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

Stimulants and Sudden Death: What Is a Physician to Do? Stimulants and Sudden Death: What Is a Physician to Do?

ABSTRACT OBJECTIVE. Recently, a US Food and Drug Administration advisory committee raised concerns about cardiovascular risks and sudden death in children and adolescents with attention-deficit/hyperactivity disorder who are receiving stimulants. METHODS. We comment on the risk of sudden death in children/adolescents taking stimulants compared with population rates, biological plausibility, and known cardiovascular effects of stimulants to determine specific risk. RESULTS. There does not seem to be higher risk of sudden death in stimulant-treated individuals compared with the general population. Although there is evidence of biological plausibility, the known effects of the stimulants on cardiovascular electrophysiology and vital signs seem to be benign. CONCLUSIONS. There does not seem to be compelling findings of a medication-specific risk necessitating changes in our stimulant treatment of children and adolescents with attention-deficit/hyperactivity disorder. The use of existing guidelines on the use of stimulants (and psychotropic agents) may identify children, adolescents, and adults who are vulnerable to sudden death. is the most common neurobehavioral disorder presenting for treatment in youth in the United States, with 3% to 9% of youth affected. 1,2 Among available treatment modalities for ADHD, pharmacotherapy is considered one of the fundamental treatments for this disorder. 3,4 Within the medication armamentarium for ADHD, stimulants (methylphenidate and amphetamine) are the most widely used and continue to be considered first-line agents. In considering the critical issue of SD, physicians, parents, and policy makers need to evaluate the evidence at hand. Specifically, we need to know first whether there is evidence of causality. This consideration involves estimating whether the risk of SD in individuals treated with stimulants exceeds that of the spontaneous risk for SD in the general population. Second, we need to assess the evidence for biological plausibility that treatment with stimulants produces dangerous cardiovascular outcomes. Against this background, clinicians should factor in the severity of the natural course of ADHD for which treatment with stimulants is being considered. STIMULANT USE AND RISK OF SD What Is the Evidence That Stimulants Increase the Risk for SD? Although tragic, SD occurs at a rare but stable rate in the general population. Estimates indicate that the risk for SD in children and adolescents is between 0.6 and 6 in 100 000 per year. 10 SD increases with age, with the risk in adults reaching upward of 1 in 1000 per year. 11 Of interest, the risk for SD in juvenile and adult athletes is higher, with SD occurring typically during the peak exercise or immediate postexercise periods. 12 SD is presumed to be of cardiac origin in half of the cases, with structural heart defects (eg, idiopathic hypertrophic subaortic stenosis) accounting for the majority of abnormalities identified, followed by anomalous origin of cardiac vessels and aortic dissection and rupture. 11 Although some retrospective data suggest that 50% of the individuals with SD had symptoms preexisting the catastrophic event including syncope, palpitations, chest pain, or dizziness; other studies have suggested that the vast majority of patients present with SD as their first and only symptom. As an important qualifier, many of the numbers used for calculation are approximations based on assumptions, use data, and spontaneous report. Data collected over the period of 1999 -2003 indicate that, using the World Health Organization classification, there have been 25 reports of SD in patients treated with stimulants: 8 of them while on methylphenidate (7 pediatric and 1 adult) and 17 of them while on amphetamine (12 pediatric and 5 adults). The adjusted rates per million prescriptions over this period for pediatric subjects was calculated to be 0.16 for methylphenidate and 0.36 for amphetamines; rates in adults were 0.07 for methylphenidate and 0.53 for amphetamine. Because of the very rare occurrences, no meaningful comparison could be made between amphetamine-and methylphenidateassociated SD. In comparing the risk for SD in stimulant-treated children and adolescents, the FDA Psychopharmacology Pediatric Advisory Board during their meeting on March 22, 2006, concluded that the stimulant medications do not pose an undue cardiovascular risk in children and adolescents. A review in stimulant-treated adults is still pending; however, a previous FDA review of the cardiovascular risk associated with the use of amphetamine in children and adults did not find undue risk other than increased risk in patients with underlying heart defects (www.fda.gov/cder/drug/advisory/adderall.htm). Another line of evidence to examine in establishing a true link between stimulants and SD is the pathophysiologic correlates of the SD. A majority of patients suffering SD during treatment with stimulants had autopsies. A structural cardiac defect was identified in 8 of 12 cases of SD during treatment with amphetamine and 4 of 7 that occurred during treatment with methylphenidate. These defects included a variety of cardiac abnormalities, with hypertrophic cardiomyopathies reported most commonly. It is important to note that autopsy evidence of cardiac anomalies requires special procedures that are not always performed, such as fine serial sectioning of 1216 WILENS et al by on March 24, 2009 www.pediatrics.org Downloaded from the myocardium. Therefore, the usefulness of a "negative" autopsy depends on the quality of the procedure. Nevertheless, the risk and distribution of the cardiac dysfunction and structural abnormalities reported in patients receiving stimulants are strikingly similar to the characteristics of SD reported in the general population 11 : half of the cases of SD in the general population were found to have structural cardiac defects at autopsy. What Is the Evidence That Stimulants Are Associated With Severe Cardiovascular Risk? A growing body of work exists about the short-and long-term effects of stimulant treatment on cardiovascular parameters in children, adolescents, and adults with ADHD who are receiving stimulants. These data, limited to healthy subjects without known preexisting cardiac anomalies, consistently demonstrate small, statistically significant, but not clinically meaningful increases in blood pressure and pulse as well as minimal changes during electrocardiography. The stimulant medications have both chronotropic (heart rate) and ionotropic (contractility) effects. Electrocardiographic effects of stimulants include predictable increases of heart rate that are rarely in the range of diagnosed tachycardia (140 beats per minute in children and 120 beats per minute in adolescents). 31 Studies indicate no changes in the PR (atrial conduction), QRS (intraventricular conduction), or QT/QTc intervals (repolarization). Conceptually, stimulants have a theoretical biological plausibility to set a cascade of events that may result in SD. However, the stimulants' relatively benign effects coupled with the lack of electrocardiographic changes (in some cases being more benign than over-the-counter and other treatments) do not seem to be sufficient to result independently in SD. Whether the stimulants interact with "vulnerable" patients such as those with presumed preexisting cardiac disease to create rhythm disturbances remains unclear, and if these disturbances are operant, they are probably occurring at an extremely low baseline rate. At the meeting on in healthy children with ADHD who are treated with stimulant medication. Moreover, the panel equated the putative risk of SD in children with ADHD who have preexisting structural abnormalities and are treated with stimulants to that of strenuous exercise in this population. Balancing the Risks The theoretical risk of using stimulants needs to be balanced against the very real risks of leaving ADHD untreated. The vast literature shows that stimulants are highly effective for ADHD

Controlled trial of high doses of pemoline for adults with attention-deficit/hyperactivity disorder

Despite the increasing awareness of attention-deficit/hyperactivity disorder (ADHD) in adults, there are a limited number of controlled pharmacologic studies of this disorder. Because the stimulant medication magnesium pemoline (Cylert, Abbott Laboratories, Abbott Park, IL) has been found effective in treating ADHD in pediatric groups, we tested its efficacy in adults with ADHD using higher daily doses than those previously studied. We conducted a 10-week, double-blind, placebo-controlled, crossover design study of pemoline at a target daily dose of 3 mg/kg per day in 35 adult patients with DSM-III-R and -IV ADHD. We used standardized structured psychiatric instruments for diagnosis. To measure improvement, we used separate assessments of ADHD, depressive, and anxiety symptoms at baseline and at each biweekly visit. ADHD outcome was determined using the ADHD symptom checklist and Clinical Global Impression scales of Severity and Improvement. Of the 35 adults with ADHD who were randomized in the trial, 27 (77%) completed the protocol. Treatment with pemoline in the final week of the 4-week active phase was best tolerated at doses substantially lower than the target dose of 3 mg/kg per day (mean dose, 2.2 mg/kg per day; mean+/-SD, 148+/-95 mg). Pemoline was significantly better at reducing ADHD symptoms compared with placebo (z = 2.4,p \u3c 0.02). Using a predefined 30% reduction in symptoms as an indication of improvement, 50% of pemoline-treated subjects and 17% of subjects in the placebo group were considered positive responders (chi2 = 7.1, p = 0.008). These results indicate that pemoline is moderately effective in the treatment of ADHD in adults. Although robust doses were targeted, most adults preferred more moderate dosing (120-160 mg/day). Given the limited efficacy, tolerability, and concerns of hepatic dysfunction, pemoline should be considered as second-line medication for treating ADHD in adults