Role of hydrodynamic factors in controlling the formation and location of unconformity-related uranium deposits: insights from reactive-flow modeling

The role of hydrodynamic factors in controlling the formation and location of unconformity-related uranium (URU) deposits in sedimentary basins during tectonically quiet periods is investigated. A number of reactive-flow modeling experiments at the deposit scale were carried out by assigning different dip angles and directions to a fault and various permeabilities to hydrostratigraphic units). The results show that the fault dip angle and direction, and permeability of the hydrostratigraphic units govern the convection pattern, temperature distribution, and uranium mineralization. Avertical fault results in uranium mineralization at the bottom of the fault within the basement, while a dipping fault leads to precipitation of uraninite below the unconformity either away from or along the plane of the fault, depending on the fault permeability. A more permeable fault causes uraninite precipitates along the fault plane,whereas a less permeable one gives rise to the precipitation of uraninite away from it. No economic ore mineralization can form when either very low or very high permeabilities are assigned to the sandstone or basement suggesting that these units seem to have an optimal window of permeability for the formation of uranium deposits. Physicochemical parameters also exert an additional control in both the location and grade of URU deposits. These results indicate that the difference in size and grade of different URU deposits may result from variation in fluid flow pattern and physicochemical conditions, caused by the change in structural features and hydraulic properties of the stratigraphic units involved

The DAC system and associations with acute leukemias and myelodysplastic syndromes

Imbalances of histone acetyltransferase (HAT) and deacetylase activity (DAC) that result in deregulated gene expression are commonly observed in leukemias. These alterations provide the basis for novel therapeutic approaches that target the epigenetic mechanisms implicated in leukemogenesis. As the acetylation status of histones has been linked to transcriptional regulation of genes involved particularly in differentiation and apoptosis, DAC inhibitors (DACi) have attracted considerable attention for treatment of hematologic malignancies. DACi encompass a structurally diverse family of compounds that are being explored as single agents as well as in combination with chemotherapeutic drugs, small molecule inhibitors of signaling pathways and hypomethylating agents. While DACi have shown clear evidence of activity in acute myeloid leukemia, myelodysplastic syndromes and lymphoid malignancies, their precise role in treatment of these different entities remain to be elucidated. Successful development of these compounds as elements of novel targeted treatment strategies for leukemia will require that clinical studies be performed in conjunction with translational research including efforts to identify predictive biomarkers

Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

<p>Abstract</p> <p>Background</p> <p>Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.</p> <p>Methods</p> <p>Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.</p> <p>Results</p> <p>The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.</p> <p>Conclusions</p> <p>We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.</p

Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Mapping age- and sex-specific HIV prevalence in adults in sub-Saharan Africa, 2000–2018

Background: Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15–59 years across SSA. Methods: We analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units. Results: We found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group. Conclusions: As the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA. © 2022, The Author(s).Funding text 1: S Afzal acknowledges support of the Pakistan Society of Medical Infectious Diseases and King Edward Medical University to access the relevant data of HIV from various sources. T W Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia (FCT), I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences - UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy - i4HB; FCT/MCTES (Ministério da Ciência, Tecnologia e Ensino Superior) through the project UIDB/50006/2020. K Deribe acknowledges support by the Wellcome Trust [grant number 201900/Z/16/Z] as part of his International Intermediate Fellowship. C Herteliu and A Pana 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. Claudiu Herteliu is partially supported by a grant of the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. Y J Kim acknowledges support by the Research Management Centre, Xiamen University Malaysia [No. XMUMRF/2020-C6/ITCM/0004]. S L Koulmane Laxminarayana acknowledges institutional support by the Manipal Academy of Higher Education. K Krishan acknowledges non-financial support from UGC Centre of Advanced Study, CAS II, Department of Anthropology, Panjab University, Chandigarh, India. M Kumar would like to acknowledge NIH/FIC K43 TW010716-04. I Landires is a member of the Sistema Nacional de Investigación (SNI), supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT), Panama. V Nuñez-Samudio is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). O O Odukoya was supported by the Fogarty International Center of the National Institutes of Health under the Award Number K43TW010704. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Z Quazi Syed acknowledges support from JNMC, Datta Meghe Institute of Medical Sciences. A I Ribeiro was supported by National Funds through FCT, under the ‘Stimulus of Scientific Employment – Individual Support’ program within the contract CEECIND/02386/2018. A M Samy acknowledges the support from a fellowship of the Egyptian Fulbright Mission program and Ain Shams University. R Shrestha acknowledges support from NIDA K01 Award: K01DA051346. N Taveira acknowledges support from FCT and Aga Khan Development Network (AKDN) - Portugal Collaborative Research Network in Portuguese speaking countries in Africa (project reference: 332821690), and by the European & Developing Countries Clinical Trials Partnership (EDCTP), UE (project reference: RIA2016MC-1615). B Unnikrishnan acknowledges support from Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal. ; Funding text 2: LBD sub-Saharan Africa HIV Prevalence Collaborators S Afzal acknowledges support of the Pakistan Society of Medical Infectious Diseases and King Edward Medical University to access the relevant data of HIV from various sources. T W Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia (FCT), I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences - UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy - i4HB; FCT/MCTES (Ministério da Ciência, Tecnologia e Ensino Superior) through the project UIDB/50006/2020. K Deribe acknowledges support by the Wellcome Trust [grant number 201900/Z/16/Z] as part of his International Intermediate Fellowship. C Herteliu and A Pana 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. Claudiu Herteliu is partially supported by a grant of the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. Y J Kim acknowledges support by the Research Management Centre, Xiamen University Malaysia [No. XMUMRF/2020-C6/ITCM/0004]. S L Koulmane Laxminarayana acknowledges institutional support by the Manipal Academy of Higher Education. K Krishan acknowledges non-financial support from UGC Centre of Advanced Study, CAS II, Department of Anthropology, Panjab University, Chandigarh, India. M Kumar would like to acknowledge NIH/FIC K43 TW010716-04. I Landires is a member of the Sistema Nacional de Investigación (SNI), supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT), Panama. V Nuñez-Samudio is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). O O Odukoya was supported by the Fogarty International Center of the National Institutes of Health under the Award Number K43TW010704. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Z Quazi Syed acknowledges support from JNMC, Datta Meghe Institute of Medical Sciences. A I Ribeiro was supported by National Funds through FCT, under the ‘Stimulus of Scientific Employment – Individual Support’ program within the contract CEECIND/02386/2018. A M Samy acknowledges the support from a fellowship of the Egyptian Fulbright Mission program and Ain Shams University. R Shrestha acknowledges support from NIDA K01 Award: K01DA051346. N Taveira acknowledges support from FCT and Aga Khan Development Network (AKDN) - Portugal Collaborative Research Network in Portuguese speaking countries in Africa (project reference: 332821690), and by the European & Developing Countries Clinical Trials Partnership (EDCTP), UE (project reference: RIA2016MC-1615). B Unnikrishnan acknowledges support from Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal.; Funding text 3: This work was primarily supported by grant OPP1132415 from the Bill & Melinda Gates Foundation. The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to publish. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. ; Funding text 4: S Afzal reports leadership or fiduciary role in other board, society, committee or advocacy group, unpaid, with the Pakistan society of Community Medicine & Public Health, the Pakistan Association of Medical Editors, and the Pakistan Society of Medical Infectious Diseases, all outside the submitted work. R Ancuceanu reports 5 payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Avvie, Sandoz, and B Braun, all outside the submitted work. T W Bärnighausen reports research grants from the European Union (Horizon 2020 and EIT Health), German Research Foundation (DFG), US National Institutes of Health, German Ministry of Education and Research, Alexander von Humboldt Foundation, Else-Kröner-Fresenius-Foundation, Wellcome Trust, Bill & Melinda Gates Foundation, KfW, UNAIDS, and WHO; consulting fees from KfW on the OSCAR initiative in Vietnam; participation on a Data Safety Monitoring Board or Advisory Board with the NIH-funded study “Healthy Options” (PIs: Smith Fawzi, Kaaya), Chair, Data Safety and Monitoring Board (DSMB), German National Committee on the “Future of Public Health Research and Education,” Chair of the scientific advisory board to the EDCTP Evaluation, Member of the UNAIDS Evaluation Expert Advisory Committee, National Institutes of Health Study Section Member on Population and Public Health Approaches to HIV/AIDS (PPAH), US National Academies of Sciences, Engineering, and Medicine’s Committee for the “Evaluation of Human Resources for Health in the Republic of Rwanda under the President’s Emergency Plan for AIDS Relief (PEPFAR),” University of Pennsylvania (UPenn) Population Aging Research Center (PARC) External Advisory Board Member; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as co-chair of the Global Health Hub Germany (which was initiated by the German Ministry of Health); all outside the submitted work. J das Neves reports grants or contracts from Ref. 13605 – Programa GÉNESE, Gilead Portugal (PGG/002/2016 – Programa GÉNESE, Gilead Portugal) outside the submitted work. L Dwyer-Lindgren reports support for the present manuscript from the Bill & Melinda Gates Foundation through grant OPP1132415. I Filip reports other financial or non-financial interests from Avicenna Medical and Clinical Research Institute, outside the submitted work. E Haeuser reports support for the present manuscript from the Bill & Melinda Gates Foundation through grant OPP1132415. C Herteliu reports grants from Romanian Ministry of Research Innovation and Digitalization, MCID, for project number ID-585-CTR-42-PFE-2021 (Jan 2022-Jun 2023) “Enhancing institutional performance through development of infrastructure and transdisciplinary research ecosystem within socio-economic domain – PERFECTIS,” from Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, for project number PN-III-P4-ID-PCCF-2016-0084 (Oct 2018-Sep 2022) “Understanding and modelling time-space patterns of psychology-related inequalities and polarization,” and project number PN-III-P2-2.1-SOL-2020-2-0351 (Jun 2020-Oct 2020) “Approaches within public health management in the context of COVID-19 pandemic,” and from the Ministry of Labour and Social Justice, Romania for project number “Agenda for skills Romania 2020-2025”; all outside the submitted work. J J Jozwiak reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Teva, Amgen, Synexus, Boehringer Ingelheim, Zentiva, and Sanofi as personal fees, all outside the submitted work. J Khubchandani reports other financial interests from Teva Pharmaceuticals, all outside the submitted work. K Krishnan reports other non-financial support from UGC Centre of Advanced Study, CAS II, Department of Anthropology, Panjab University, Chandigarh, India, outside the submitted work. H J Larson reports grants or contracts from the MacArthur Foundation and Merck to London School of Hygeine and Tropical Medicine, and from the Vaccine Confidence Fund to the University of Washington; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Center for Strategic and International Studies as payment to LSHTM for co-chairing HighLevel Panel and from GSK as personal payment for developing training sessions and lectures; leadership or fiduciary role in other board, society, committee or advocacy group, pair, with the ApiJect Advisory Board; all outside the submitted work. O O Odukoya reports support for the present manuscript from the Fogarty International Center of the National Institutes of Health under the Award Number K43TW010704. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A Pans reports grants from Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, for project number PN-III-P4-ID-PCCF-2016-0084 (Oct 2018-Sep 2022) “Understanding and modelling time-space patterns of psychology-related inequalities and polarization,” and project number PN-III-P2-2.1-SOL-2020-2-0351 (Jun 2020-Oct 2020) “Approaches within public health management in the context of COVID-19 pandemic,” outside the submitted work. S R Pandi-Perumal reports royalties from Springer for editing services; stock or stock options in Somnogen Canada Inc as the President and Chief Executive Officer; all outside the submitted work. A Radfar reports other financial or non-financial interests from Avicenna Medical and Clinical Research Institute, outside the submitted work. A I Ribeiro reports grants or contracts from National Funds through FCT, under the ‘Stimulus of Scientific Employment – Individual Support’ program within the contract CEECIND/02386/2018, outside the submitted work. J M Ross reports support for the present manuscript from the Bill & Melinda Gates Foundation through grant OPP1132415; grants or contracts from National Institutes of Health and Firland Foundation as payments to their institution; consulting fees from United States Agency for International Development as personal payments, and from KNCV Tuberculosis Foundation as payments to their institution; all outside the submitted work. E Rubagotti reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Greenwich China Office and Unviersity Prince Mohammad VI, Morocco, all outside the submitted work. B Sartorius reports grants or contracts from DHSC – GRAM Project; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as a member of the GBD Scientific Council and a Member of WHO RGHS; all outside the submitted work. J A Singh reports consulting fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two labs Inc, Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, MedIQ, Jupiter Life Science LLC, UBM LLC, Trio Health, Medscape, WebMD, and Practice Point communications, and the National Institutes of Health and the American College of Rheumatology; payment or honoraria for participating in the speakers bureau for Simply Speaking; support for attending meetings and/or travel from the steering committee of OMERACT, to attend their meeting every 2 years; participation on a Data Safety Monitoring Board or Advisory Board as an unpaid member of the FDA Arthritis Advisory Committee; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as a member of the steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arm’s length funding from 12 pharmaceutical companies, with the Veterans Affairs Rheumatology Field Advisory Committee as Chair, and with the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis as a director and editor; stock or stock options in TPT Global Tech, Vaxart pharmaceuticals, Atyu Biopharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris Pharmaceuticals, Enzolytics Inc, Series Therapeutics, Tonix Pharmaceuticals, and Charlotte’s Web Holdings Inc. and previously owned stock options in Amarin, Viking, and Moderna pharmaceuticals; all outside the submitted work. N Taveira reports grants or contracts from FCT and Aga Khan Development Network (AKDN) – Portugal Collaborative Research Network in Portuguese speaking countries in Africa (Project reference: 332821690) and from European & Developing Countries Clinical Trials Partnership (EDCTP), UE (Project reference: RIA2016MC-1615), as payments made to their institution, all outside the submitted work

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Global, regional, and national mortality among young people aged 10–24 years, 1950–2019: a systematic analysis for the Global Burden of Disease Study 2019

Summary: Background Documentation of patterns and long-term trends in mortality in young people, which reflect huge changes in demographic and social determinants of adolescent health, enables identification of global investment priorities for this age group. We aimed to analyse data on the number of deaths, years of life lost, and mortality rates by sex and age group in people aged 10–24 years in 204 countries and territories from 1950 to 2019 by use of estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Methods We report trends in estimated total numbers of deaths and mortality rate per 100 000 population in young people aged 10–24 years by age group (10–14 years, 15–19 years, and 20–24 years) and sex in 204 countries and territories between 1950 and 2019 for all causes, and between 1980 and 2019 by cause of death. We analyse variation in outcomes by region, age group, and sex, and compare annual rate of change in mortality in young people aged 10–24 years with that in children aged 0–9 years from 1990 to 2019. We then analyse the association between mortality in people aged 10–24 years and socioeconomic development using the GBD Socio-demographic Index (SDI), a composite measure based on average national educational attainment in people older than 15 years, total fertility rate in people younger than 25 years, and income per capita. We assess the association between SDI and all-cause mortality in 2019, and analyse the ratio of observed to expected mortality by SDI using the most recent available data release (2017). Findings In 2019 there were 1·49 million deaths (95% uncertainty interval 1·39–1·59) worldwide in people aged 10–24 years, of which 61% occurred in males. 32·7% of all adolescent deaths were due to transport injuries, unintentional injuries, or interpersonal violence and conflict; 32·1% were due to communicable, nutritional, or maternal causes; 27·0% were due to non-communicable diseases; and 8·2% were due to self-harm. Since 1950, deaths in this age group decreased by 30·0% in females and 15·3% in males, and sex-based differences in mortality rate have widened in most regions of the world. Geographical variation has also increased, particularly in people aged 10–14 years. Since 1980, communicable and maternal causes of death have decreased sharply as a proportion of total deaths in most GBD super-regions, but remain some of the most common causes in sub-Saharan Africa and south Asia, where more than half of all adolescent deaths occur. Annual percentage decrease in all-cause mortality rate since 1990 in adolescents aged 15–19 years was 1·3% in males and 1·6% in females, almost half that of males aged 1–4 years (2·4%), and around a third less than in females aged 1–4 years (2·5%). The proportion of global deaths in people aged 0–24 years that occurred in people aged 10–24 years more than doubled between 1950 and 2019, from 9·5% to 21·6%. Interpretation Variation in adolescent mortality between countries and by sex is widening, driven by poor progress in reducing deaths in males and older adolescents. Improving global adolescent mortality will require action to address the specific vulnerabilities of this age group, which are being overlooked. Furthermore, indirect effects of the COVID-19 pandemic are likely to jeopardise efforts to improve health outcomes including mortality in young people aged 10–24 years. There is an urgent need to respond to the changing global burden of adolescent mortality, address inequities where they occur, and improve the availability and quality of primary mortality data in this age group

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe