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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Using a sample of 1.31×109 J/ψ events collected by the BESIII detector at BEPCII during 2009 and 2012, we study the J/ψ→ωη′π+π− hadronic process. For the first time, we measure the branching ratio B(J/ψ→ωη′π+π−)=(1.12±0.02±0.13)×10−3. We search for the X(1835) state in the η′π+π− invariant mass spectra. No evidence is found and we estimate the upper limit on the branching fraction at 90% confidence level to be B(J/ψ→ωX(1835),X(1835)→η′π+π−)<6.2×10−5.
Several intermediate states of the reaction channels 𝑒+𝑒−→𝜋+𝜋−𝐷0¯𝐷0 and 𝑒+𝑒−→𝜋+𝜋−𝐷+𝐷− are studied using the data samples collected with the BESIII detector at center-of-mass energies above 4.08 GeV. For the first time in this final state, a 𝜓(3770) signal is seen in the 𝐷¯𝐷 invariant mass spectrum, with a statistical significance of 5.2𝜎 at √𝑠=4.42 GeV. There is also evidence for this resonance at √𝑠=4.26 and 4.36 GeV with statistical significance of 3.2𝜎 and 3.3𝜎, respectively. In addition, the Born cross section of 𝑒+𝑒−→𝜋+𝜋−𝜓(3770) is measured. The proposed heavy-quark-spin-symmetry partner of the 𝑋(3872), the state 𝑋2(4013), is also searched for in the 𝐷¯𝐷 invariant mass spectra. No obvious signal is found. The upper limit of the Born cross section of the process 𝑒+𝑒−→𝜌0𝑋2(4013) combined with the branching fraction is measured. Also, the processes 𝑒+𝑒−→𝐷1(2420)¯𝐷+c.c. are investigated. The neutral mode with 𝐷1(2420)0→𝐷0𝜋+𝜋− is reported with statistical significance of 7.4𝜎 at √𝑠=4.42 GeV for the first time, and evidence with statistical significance of 3.2𝜎 and 3.3𝜎 at √𝑠=4.36 and 4.60 GeV is seen, respectively. No evident signal for the process 𝑒+𝑒−→𝐷1(2420)0¯𝐷0+c.c.,𝐷1(2420)0→𝐷*+𝜋− is reported. Evidence for 𝑒+𝑒−→𝐷1(2420)+𝐷−+c.c.,𝐷1(2420)+→𝐷+𝜋+𝜋− is reported with statistical significance of 3.1𝜎 and 3.0𝜎 at √𝑠=4.36 and 4.42 GeV, respectively.
The SU(3)-flavor violating decay J/ψ→Ξ(1530)−Ξ¯++c.c. is studied using (1310.6±7.0)×106 J/ψ events collected with the BESIII detector at BEPCII and the branching fraction is measured to be B(J/ψ→Ξ(1530)−Ξ¯++c.c.) = (3.17±0.02stat.±0.08syst.)×10−4. This is consistent with previous measurements with an improved precision. The angular parameter for this decay is measured for the first time and is found to be α=−0.21±0.04stat.±0.06syst.. In addition, we report evidence for the radiative decay Ξ(1530)−→γΞ− with a significance of 3.9σ, including the systematic uncertainties. The 90\% confidence level upper limit on the branching fraction is determined to be B(Ξ(1530)−→γΞ−)≤3.7\%.
Using a total of 11.0 fb−1 of e+e− collision data with center-of-mass energies between 4.009 GeV and 4.6 GeV and collected with the BESIII detector at BEPCII, we measure fifteen exclusive cross sections and effective form factors for the process e+e−→Ξ−Ξ¯+ by means of a single baryon-tag method. After performing a fit to the dressed cross section of e+e−→Ξ−Ξ¯+, no significant ψ(4230) or ψ(4260) resonance is observed in the Ξ−Ξ¯+ final states, and upper limits at the 90\% confidence level on ΓeeB for the processes ψ(4230)/ψ(4260)→Ξ−Ξ¯+ are determined. In addition, an excited Ξ baryon at 1820 MeV/c2 is observed with a statistical significance of 6.2 ∼ 6.5σ by including the systematic uncertainty, and the mass and width are measured to be M=(1825.5±4.7±4.7)~MeV/c2 and Γ=(17.0±15.0±7.9)~MeV, which confirms the existence of the JP=32− state Ξ(1820).
Using a total of 9.0 fb−1 of e+e− collision data with center-of-mass energies between 4.15 and 4.30 GeV collected by the BESIII detector, we search for the processes e+e−→γX(3872) with X(3872)→π0χcJ for J=0,1,2. We report the first observation of X(3872)→π0χc1, a new decay mode of the X(3872), with a statistical significance of more than 5σ. Normalizing to the previously established process e+e−→γX(3872) with X(3872)→π+π−J/ψ, we find B(X(3872)→π0χc1)/B(X(3872)→π+π−J/ψ)=0.88+0.33−0.27±0.10, where the first error is statistical and the second is systematic. We set 90% confidence level upper limits on the corresponding ratios for the decays to π0χc0 and π0χc2 of 19 and 1.1, respectively.
Using 448.1 × 106 ψ(3686) events collected with the BESIII detector at BEPCII, we employ a single-baryon tagging technique to make the first observation of ψ(3686) → Ξ(1530)−Ξ¯(1530)+ and Ξ(1530)−Ξ¯+ decays with a statistical significance of more than 10σ and 5.0σ, respectively. The branching fractions are measured to be B[ψ(3686)→Ξ(1530)−Ξ¯(1530)+] = (11.45 ± 0.40 ± 0.59) × 10−5 and B[ψ(3686)→Ξ(1530)−Ξ¯+] = (0.70 ± 0.11 ± 0.04) × 10−5. The angular distribution parameter for ψ(3686) → Ξ(1530)−Ξ¯(1530)+ is determined to be α = 0.40 ± 0.24 ± 0.06, which agrees with the theoretical predictions within 1σ. The first uncertainties are statistical, and the second systematic.
The Born cross section for the process e+e−→pp¯ is measured using the initial state radiation technique with an undetected photon. This analysis is based on datasets corresponding to an integrated luminosity of 7.5 fb−1, collected with the BESIII detector at the BEPCII collider at center of mass energies between 3.773 and 4.600 GeV. The Born cross section for the process e+e−→pp¯ and the proton effective form factor are determined in the pp¯ invariant mass range between 2.0 and 3.8 GeV/c2 divided into 30 intervals. The proton form factor ratio (|GE|/|GM|) is measured in 3 intervals of the pp¯ invariant mass between 2.0 and 3.0 GeV/c2.
Using a data sample of (448.1±2.9)×106 ψ(3686) decays collected by the BESIII detector at the Beijing Electron Positron Collider (BEPCII), we observe the decays χcJ→ϕϕη (J=0, 1, 2), where the χcJ are produced via the radiative processes ψ(3686)→γχcJ. The branching fractions are measured to be B(χc0→ϕϕη)=(8.41±0.74±0.62)×10−4, B(χc1→ϕϕη)=(2.96±0.43±0.22)×10−4, and B(χc2→ϕϕη)=(5.33±0.52±0.39)×10−4, where the first uncertainties are statistical and the second are systematic. We also search for intermediate states in the ϕϕ or ηϕ combinations, but no significant structure is seen due to the limited statistics.
We report the first observation of D+→τ+ντ with a significance of 5.1σ. We measure B(D+→τ+ντ)=(1.20±0.24stat.±0.12syst.)×10−3. Taking the world average B(D+→μ+νμ)=(3.74±0.17)×10−4, we obtain Rτ/μ=Γ(D+→τ+ντ)/Γ(D+→μ+νμ)=3.21±0.64stat.±0.43syst., which is consistent with the Standard Model expectation of lepton flavor universality. Using external inputs, our results give values for the D+ decay constant fD+ and the CKM matrix element |Vcd| that are consistent with, but less precise than, other determinations.
A search for the rare radiative leptonic decay D+s→γe+νe is performed for the first time using electron-positron collision data corresponding to an integrated luminosity of 3.19 fb−1, collected with the BESIII detector at a center-of-mass energy of 4.178 GeV. No evidence for the D+s→γe+νe decay is seen and an upper limit of B(D+s→γe+νe)<1.3×10−4 is set on the partial branching fraction at a 90\% confidence level for radiative photon energies E∗γ>0.01~GeV.
By analyzing 6.32 fb − 1 of e+ e− annihilation data collected at the center-of-mass energies between 4.178 and 4.226 GeV with the BESIII detector, we determine the branching fraction of the leptonic decay D + s → τ + ντ, with τ+ → π + π0¯ντ, to be B D + s → τ + ν τ = (5.29 ± 0.25 stat ± 0.20 syst) %. We estimate the product of the Cabibbo-Kobayashi-Maskawa matrix element |Vcs|and the D + s decay constant f D + s to be f D + s|Vcs| = (244.8 ± 5.8 stat ± 4.8syst) MeV, using the known values of the τ + and D + s masses as well as the D + s lifetime, together with our branching fraction measurement. Combining the value of |Vcs| obtained from a global fit in the standard model and f D + s from lattice quantum chromodynamics, we obtain f D + s = (251.6 ± 5.9 stat ± 4.9syst) MeV and |Vcs| = 0.980 ± 0.023 stat ± 0.019 syst. Using the branching fraction of B D + s → μ + νμ = (5.35±0.21)×10−3, we obtain the ratio of the branching fractions B D + s → τ + ντ/B D +s → μ+νμ = 9.89±0.71, which is consistent with the standard model prediction of lepton flavor universality.
The baryonic decay D+s→pn¯ is observed, and the corresponding branching fraction is measured to be (1.21±0.10±0.05)×10−3, where the first uncertainty is statistical and second systematic. The data sample used in this analysis was collected with the BESIII detector operating at the BEPCII e+e− double-ring collider with a center-of-mass energy of 4.178~GeV and an integrated luminosity of 3.19~fb−1. The result confirms the previous measurement by the CLEO Collaboration and is of greatly improved precision, which may deepen our understanding of the dynamical enhancement of the W-annihilation topology in the charmed meson decays.
We report a measurement of the observed cross sections of e+ e− → J/ψX based on 3.21 fb − 1 of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686) → J/ψX) = (64.4 ± 0.6 ± 1.6)% and B(ψ(3770) → J/ψX) = (0.5 ± 0.2 ± 0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ (3686) → J/ψX and ψ(3770) → J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→ J/ψX. Under this assumption, we extracted the R (3760) mass M R (3760 ) = 3766.2 ± 3.8 ± 0.4 MeV/c2, total width Γ tot R ( 3760 ) = 22.2 ± 5.9 ± 1.4 MeV, and product of leptonic width and decay branching fraction
ΓeeR(3760) B[R(3760) → J/ψX] = (79.4 ± 85.5 ± 11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.
We search for rare decays of D mesons to hadrons accompany with an electron-positron pair (h(h')e+e−), using an e+e− collision sample corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at s√ = 3.773 GeV. No significant signals are observed, and the corresponding upper limits on the branching fractions at the 90% confidence level are determined. The sensitivities of the results are at the level of 10−5∼10−6, providing a large improvement over previous searches.
Based on a data sample of (448.1±2.9)×106 ψ(3686) decays collected with the BESIII experiment, a search for the flavor changing neutral current transition ψ(3686) → Λ+cp¯¯¯e+e−+c.c. is performed for the first time. No signal candidates are observed and the upper limit on the branching fraction of ψ(3686) → Λ+cp¯¯¯e+e− is determined to be 1.7×10−6 at the 90\% confidence level. The result is consistent with expectations from the Standard Model, and no evidence for new physics is found.
Using an e+e− annihilation data sample corresponding to an integrated luminosity of 2.93fb−1 collected at the center-of-mass energy of 3.773\,GeV with the BESIII detector, we measure the absolute branching fractions of D+→ηηπ+, D+→ηπ+π0, and D0→ηπ+π− to be (2.96±0.24±0.13)×10−3, (2.23±0.15±0.11)×10−3, and (1.20±0.07±0.04)×10−3, respectively, where the first uncertainties are statistical and the second ones systematic. The D+→ηηπ+ decay is observed for the first time and the branching fractions of D+(0)→ηπ+π0(−) are measured with much improved precision. In addition we test for CP asymmetries in the separated charge-conjugate branching fractions; no evidence of CP violation is found.
Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence.
Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon.
Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n = 38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study.
Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon.
Trial Registration: ClinicalTrials.gov Identifier: NCT00725777
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
Background The COVID-19 pandemic has spurred large-scale, inter-institutional research efforts. To enable these efforts, researchers must agree on dataset definitions that not only cover all elements relevant to the respective medical specialty but that are also syntactically and semantically interoperable. Following such an effort, the German Corona Consensus (GECCO) dataset has been developed previously as a harmonized, interoperable collection of the most relevant data elements for COVID-19-related patient research. As GECCO has been developed as a compact core dataset across all medical fields, the focused research within particular medical domains demands the definition of extension modules that include those data elements that are most relevant to the research performed in these individual medical specialties.
Objective To (i) specify a workflow for the development of interoperable dataset definitions that involves a close collaboration between medical experts and information scientists and to (ii) apply the workflow to develop dataset definitions that include data elements most relevant to COVID-19-related patient research in immunization, pediatrics, and cardiology.
Methods We developed a workflow to create dataset definitions that are (i) content-wise as relevant as possible to a specific field of study and (ii) universally usable across computer systems, institutions, and countries, i.e., interoperable. We then gathered medical experts from three specialties (immunization, pediatrics, and cardiology) to the select data elements most relevant to COVID-19-related patient research in the respective specialty. We mapped the data elements to international standardized vocabularies and created data exchange specifications using HL7 FHIR. All steps were performed in close interdisciplinary collaboration between medical domain experts and medical information scientists. The profiles and vocabulary mappings were syntactically and semantically validated in a two-stage process.
Results We created GECCO extension modules for the immunization, pediatrics, and cardiology domains with respect to the pandemic requests. The data elements included in each of these modules were selected according to the here developed consensus-based workflow by medical experts from the respective specialty to ensure that the contents are aligned with the respective research needs. We defined dataset specifications for a total number of 48 (immunization), 150 (pediatrics), and 52 (cardiology) data elements that complement the GECCO core dataset. We created and published implementation guides and example implementations as well as dataset annotations for each extension module.
Conclusions These here presented GECCO extension modules, which contain data elements most relevant to COVID-19-related patient research in immunization, pediatrics and cardiology, were defined in an interdisciplinary, iterative, consensus-based workflow that may serve as a blueprint for the development of further dataset definitions. The GECCO extension modules provide a standardized and harmonized definition of specialty-related datasets that can help to enable inter-institutional and cross-country COVID-19 research in these specialties.
Background: The COVID-19 pandemic has spurred large-scale, inter-institutional research efforts. To enable these efforts, the German Corona Consensus (GECCO) dataset has been developed previously as a harmonized, interoperable collection of the most relevant data elements for COVID-19-related patient research. As GECCO has been developed as a compact core dataset across all medical fields, the focused research within particular medical domains demanded the definition of extension modules that include those data elements that are most relevant to the research performed in these individual medical specialties.
Main body: We created GECCO extension modules for the immunization, pediatrics, and cardiology domains with respect to the pandemic requests. The data elements included in each of these modules were selected in a consensus-based process by working groups of medical experts from the respective specialty to ensure that the contents are aligned with the research needs of the specialty. The selected data elements were mapped to international standardized vocabularies and data exchange specifications were created using HL7 FHIR profiles on the appropriate resources. All steps were performed in close interdisciplinary collaboration between medical domain experts, medical information scientists and FHIR developers. The profiles and vocabulary mappings were syntactically and semantically validated in a two-stage process. In that way, we defined dataset specifications for a total number of 23 (immunization), 59 (pediatrics), and 50 (cardiology) data elements that augment the GECCO core dataset. We created and published implementation guides and example implementations as well as dataset annotations for each extension module.
Conclusions: We here present extension modules for the GECCO core dataset that contain data elements most relevant to COVID-19-related patient research in immunization, pediatrics and cardiology. These extension modules were defined in an interdisciplinary, iterative, consensus-based approach that may serve as a blueprint for the development of further dataset definitions and GECCO extension modules. The here developed GECCO extension modules provide a standardized and harmonized definition of specialty-related datasets that can help to enable inter-institutional and cross-country COVID-19 research in these specialties.