Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

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. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Measurement of charged particle spectra in minimum-bias events from proton-proton collisions at root s =13 TeV

Pseudorapidity, transverse momentum, and multiplicity distributions are measured in the pseudorapidity range vertical bar eta vertical bar 0.5 GeV in proton-proton collisions at a center-of-mass energy of root s = 13 TeV. Measurements are presented in three different event categories. The most inclusive of the categories corresponds to an inelastic pp data set, while the other two categories are exclusive subsets of the inelastic sample that are either enhanced or depleted in single diffractive dissociation events. The measurements are compared to predictions from Monte Carlo event generators used to describe high-energy hadronic interactions in collider and cosmic-ray physics.Peer reviewe

Measurement of the CP-violating phase phi_s in the Bs0→^0_\mathrm{s}\to J/ψ ϕ/\psi\, \phi(1020) →μ+μ−\to \mu^+\mu^-K+^+K−^- channel in proton-proton collisions at s=\sqrt{s} = 13 TeV

The CP-violating weak phase ?s and the decay width difference ??s between the light and heavy B0s mass eigenstates are measured with the CMS detector at the LHC in a sample of 48 500 reconstructed B0s? J/I) d (1020) ?11+11? K+K? events. The measurement is based on a data sample corresponding to an integrated luminosity of 96.4 fb?1, collected in proton-proton collisions at ?s = 13 TeV in 2017?2018. To extract the values of ?s and ??s, a time-dependent and flavor-tagged angular analysis of the 11+11?K+K? final state is performed. The analysis employs a dedicated tagging trigger and a novel opposite-side muon flavor tagger based on machine learning techniques. The measurement yields ?s = ?11 ?50 (stat) ? 10 (syst) mrad and ??s = 0.114 ? 0.014 (stat)? 0.007 (syst) ps?1, in agreement with the standard model predictions. When combined with the previous CMS measurement at ?s = 8 TeV, the following values are obtained: ?s = ?21 ? 44 (stat) ? 10 (syst) mrad, ??s = 0.1032 ? 0.0095 (stat) ? 0.0048 (syst) ps?1, a significant improvement over the 8 TeV result. ? 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY licens

Measurement of the C P-violating phase φs in the B0 s → J/ψφ(1020) → μ+μ− K+K− channel in proton-proton collisions at √s = 13 TeV

The C P-violating weak phase φs and the decay width difference s between the light and heavy B0 s mass eigenstates are measured with the CMS detector at the LHC in a sample of 48 500 reconstructed B0 s → J/ψ φ(1020) → μ+μ− K+K− events. The measurement is based on a data sample corresponding to an integrated luminosity of 96.4 fb−1, collected in proton-proton collisions at √s = 13 TeV in 2017–2018. To extract the values of φs and s, a time-dependent and flavor-tagged angular analysis of the μ+μ−K+K− final state is performed. The analysis employs a dedicated tagging trigger and a novel opposite-side muon flavor tagger based on machine learning techniques. The measurement yields φs = −11±50 (stat)±10 (syst) mrad and s = 0.114±0.014 (stat)±0.007 (syst) ps−1, in agreement with the standard model predictions. When combined with the previous CMS measurement at √s = 8 TeV, the following values are obtained: φs = −21 ± 44 (stat) ± 10 (syst) mrad, s = 0.1032 ± 0.0095 (stat) ± 0.0048 (syst) ps−1, a significant improvement over the 8 TeV result

Search for heavy resonances decaying to WW, WZ, or WH boson pairs in a final state consisting of a lepton and a large-radius jet in proton-proton collisions at s =13 TeV

A search for new heavy resonances decaying to pairs of bosons (WW, WZ, or WH) is presented. The analysis uses data from proton-proton collisions collected with the CMS detector at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 137 fb(-1). One of the bosons is required to be a W boson decaying to an electron or muon and a neutrino, while the other boson is required to be reconstructed as a single jet with mass and substructure compatible with a quark pair from a W, Z, or Higgs boson decay. The search is performed in the resonance mass range between 1.0 and 4.5 TeVand includes a specific search for resonances produced via vector boson fusion. The signal is extracted using a twodimensional maximum likelihood fit to the jet mass and the diboson invariant mass distributions. No significant excess is observed above the estimated background. Model-independent upper limits on the production cross sections of spin-0, spin-1, and spin-2 heavy resonances are derived as functions of the resonance mass and are interpreted in the context of bulk radion, heavy vector triplet, and bulk graviton models. The reported bounds are the most stringent to date

Fragmentation of jets containing a prompt J/psi meson in PbPb and pp collisions at root s(NN)=5.02 TeV

Jets containing a prompt J/ψ meson are studied in lead-lead collisions at a nucleon-nucleon center-ofmass energy of 5.02 TeV, using the CMS detector at the LHC. Jets are selected to be in the transverse momentum range of 30 < pT < 40 GeV. The J/ψ yield in these jets is evaluated as a function of the jet fragmentation variable z, the ratio of the J/ψ pT to the jet pT. The nuclear modification factor, RAA, is then derived by comparing the yield in lead-lead collisions to the corresponding expectation based on proton-proton data, at the same nucleon-nucleon center-of-mass energy. The suppression of the J/ψ yield shows a dependence on z, indicating that the interaction of the J/ψ with the quark-gluon plasma formed in heavy ion collisions depends on the fragmentation that gives rise to the J/ψ meson

Observation of B<inf>s</inf>⁰ mesons and measurement of the B<inf>s</inf>⁰/B⁺ yield ratio in PbPb collisions at [Formula presented] TeV

The Bs0 and B+ production yields are measured in PbPb collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data sample, collected with the CMS detector at the LHC, corresponds to an integrated luminosity of 1.7 nb−1. The mesons are reconstructed in the exclusive decay channels B→s0J/ψ(μ+μ−)ϕ(K+K−) and B→+J/ψ(μ+μ−)K+, in the transverse momentum range 7–50 GeV/c and absolute rapidity 0–2.4. The Bs0 meson is observed with a statistical significance in excess of five standard deviations for the first time in nucleus-nucleus collisions. The measurements are performed as functions of the transverse momentum of the B mesons and of the PbPb collision centrality. The ratio of production yields of Bs0 and B+ is measured and compared to theoretical models that include quark recombination effects