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Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness.
Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively.
Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD.
Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.
Background: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy.
Methods: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9–10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5–9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect.
Discussion: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery.
Trial registration: ClinicalTrials.gov (identifier: NCT03369210).
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Photolabile protecting groups are widely used to trigger oligonucleotide activity. The ON/OFF‐amplitude is a critical parameter. An experimental setup has been developed to identify protecting group derivatives with superior caging properties. Bulky rests are attached to the cage moiety via Cu‐catalyzed azide–alkyne cycloaddition post‐synthetically on DNA. Interestingly, the decrease in melting temperature upon introducing o‐nitrobenzyl‐caged (NPBY‐) and diethylaminocoumarin‐cages (DEACM‐) in DNA duplexes reaches a limiting value. NMR spectroscopy was used to characterize individual base‐pair stabilities and determine experimental structures of a selected number of photocaged DNA molecules. The experimental structures agree well with structures predicted by MD simulations. Combined, the structural data indicate that once a sterically demanding group is added to generate a tri‐substituted carbon, the sterically less demanding cage moiety points towards the neighboring nucleoside and the bulkier substituents remain in the major groove.
We measure the inclusive semielectronic decay branching fraction of the D+s meson. A double-tag technique is applied to e+e− annihilation data collected by the BESIII experiment at the BEPCII collider, operating in the center-of-mass energy range 4.178–4.230 GeV. We select positrons fromD+s→Xe+νe with momenta greater than 200 MeV/c and determine the laboratory momentum spectrum, accounting for the effects of detector efficiency and resolution. The total positron yield and semielectronic branching fraction are determined by extrapolating this spectrum below the momentum cutoff. We measure the D+s semielectronic branching fraction to be(6.30±0.13(stat.)±0.09(syst.)±0.04(ext.))%, showing no evidence for unobserved exclusive semielectronic modes. We combine this result with external data taken from literature to determine the ratio of the D+s and D0 semielectronic widths, Γ(D+s→Xe+νe)Γ(D0→Xe+νe)=0.790±0.016(stat.)±0.011(syst.)±0.016(ext.). Our results are consistent with and more precise than previous measurements.
The Born cross sections and effective form factors for process 𝑒+𝑒−→Ξ−¯Ξ+ are measured at eight center-of-mass energies between 2.644 and 3.080 GeV, using a total integrated luminosity of 363.9 pb−1 𝑒+𝑒− collision data collected with the BESIII detector at BEPCII. After performing a fit to the Born cross section of 𝑒+𝑒−→Ξ−¯Ξ+, no significant threshold effect is observed.
The process e+e−→ϕη is studied at 22 center-of-mass energy points (√s) between 2.00 and 3.08 GeV using 715 pb−1 of data collected with the BESIII detector. The measured Born cross section of e+e−→ϕη is found to be consistent with BABAR measurements, but with improved precision. A resonant structure around 2.175 GeV is observed with a significance of 6.9σ with mass (2163.5±6.2±3.0) MeV/c2 and width (31.1+21.1−11.6±1.1) MeV, where the first uncertainties are statistical and the second are systematic.
Using 10.1 × 109 J/ψ events produced by the Beijing Electron Positron Collider (BEPCII) at a center-of-mass energy √s = 3.097 GeV and collected with the BESIII detector, we present a search for the rare semi-leptonic decay J/ψ → D−e+νe + c.c. No excess of signal above background is observed, and an upper limit on the branching fraction ℬ(J/ψ → D−e+νe + c. c.) < 7.1 × 10−8 is obtained at 90% confidence level. This is an improvement of more than two orders of magnitude over the previous best limit.
Though immensely successful, the standard model of particle physics does not offer any explanation as to why our Universe contains so much more matter than antimatter. A key to a dynamically generated matter–antimatter asymmetry is the existence of processes that violate the combined charge conjugation and parity (CP) symmetry1. As such, precision tests of CP symmetry may be used to search for physics beyond the standard model. However, hadrons decay through an interplay of strong and weak processes, quantified in terms of relative phases between the amplitudes. Although previous experiments constructed CP observables that depend on both strong and weak phases, we present an approach where sequential two-body decays of entangled multi-strange baryon–antibaryon pairs provide a separation between these phases. Our method, exploiting spin entanglement between the double-strange Ξ− baryon and its antiparticle2 Ξ¯+
, has enabled a direct determination of the weak-phase difference, (ξP − ξS) = (1.2 ± 3.4 ± 0.8) × 10−2 rad. Furthermore, three independent CP observables can be constructed from our measured parameters. The precision in the estimated parameters for a given data sample size is several orders of magnitude greater than achieved with previous methods3. Finally, we provide an independent measurement of the recently debated Λ decay parameter αΛ (refs. 4,5). The ΛΛ¯
asymmetry is in agreement with and compatible in precision to the most precise previous measurement.
Using a sample of (10.09±0.04)×109 J/ψ events collected with the BESIII detector, a partial wave analysis of J/ψ→γη′η′ is performed.The masses and widths of the observed resonances and their branching fractions are reported. The main contribution is from J/ψ→γf0(2020) with f0(2020)→η′η′, which is found with a significance of greater than 25σ. The product branching fraction B(J/ψ → γf0(2020))⋅B(f0(2020) → η′η′ is measured to be (2.63±0.06(stat.) + 0.31−0.46(syst.))×10−4.
Based on an e+e− collision data sample corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at √s=3.773 GeV, the first amplitude analysis of the singly Cabibbo-suppressed decay D+→K+K0Sπ0 is performed. From the amplitude analysis, the K∗(892)+K0S component is found to be dominant with a fraction of (57.1±2.6±4.2)%, where the first uncertainty is statistical and the second systematic. In combination with the absolute branching fraction B(D+→K+K0Sπ0) measured by BESIII, we obtain B(D+→K∗(892)+K0S)=(8.69±0.40±0.64±0.51)×10−3, where the third uncertainty is due to the branching fraction B(D+→K+K0Sπ0). The precision of this result is significantly improved compared to the previous measurement. This result also differs from most of theoretical predictions by about 4σ, which may help to improve the understanding of the dynamics behind.
We present the first experimental search for the rare charm decay D0→π0ν¯ν. It is based on an e+e− collision sample consisting of 10.6×10^6 pairs of D0¯D0 mesons collected by the BESIII detector at √s=3.773 GeV, corresponding to an integrated luminosity of 2.93 fb^−1. A data-driven method is used to ensure the reliability of the background modeling. No significant D0→π0ν¯ν signal is observed in data and an upper limit of the branching fraction is set to be 2.1×10^-4 at the 90% confidence level. This is the first experimental constraint on charmed-hadron decays into dineutrino final states.
A search for the charged lepton flavor violating decay 𝐽/𝜓→𝑒±𝜏∓ with 𝜏∓→𝜋∓𝜋0𝜈𝜏 is performed with about 10×109 𝐽/𝜓 events collected with the BESIII detector at the BEPCII. No significant signal is observed, and an upper limit is set on the branching fraction ℬ(𝐽/𝜓→𝑒±𝜏∓)<7.5×10−8 at the 90% confidence level. This improves the previously published limit by two orders of magnitude.
By analyzing an e+e− annihilation data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, we measure the branching fraction of the D0→ρ−μ+νμ decay for the first time. We obtain BD0→ρ−μ+νμ=(1.35±0.09stat±0.09syst)×10−3. Using the world average of BD0→ρ−e+νe, we find a branching fraction ratio of BD0→ρ−μ+νμ/BD0→ρ−e+νe=0.90±0.11, which agrees with the theoretical expectation of lepton flavor universality within the uncertainty. Combining the world average of BD+→ρ0μ+νμ and the lifetimes of D0(+), we obtain a partial decay width ratio of ΓD0→ρ−μ+νμ/(2ΓD+→ρ0μ+νμ)=0.71±0.14, which is consistent with the isospin symmetry expectation of one within 2.1σ. For the reported values of BD0→ρ−μ+νμ/BD0→ρ−e+νe and ΓD0→ρ−μ+νμ/2ΓD+→ρ0μ+νμ, the uncertainty is the quadratic sum of the statistical and systematic uncertainties.
By analyzing an e+e− annihilation data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, we measure the branching fraction of the D0→ρ−μ+νμ decay for the first time. We obtain BD0→ρ−μ+νμ=(1.35±0.09stat±0.09syst)×10−3. Using the world average of BD0→ρ−e+νe, we find a branching fraction ratio of BD0→ρ−μ+νμ/BD0→ρ−e+νe=0.90±0.11, which agrees with the theoretical expectation of lepton flavor universality within the uncertainty. Combining the world average of BD+→ρ0μ+νμ and the lifetimes of D0(+), we obtain a partial decay width ratio of ΓD0→ρ−μ+νμ/(2ΓD+→ρ0μ+νμ)=0.71±0.14, which is consistent with the isospin symmetry expectation of one within 2.1σ. For the reported values of BD0→ρ−μ+νμ/BD0→ρ−e+νe and ΓD0→ρ−μ+νμ/2ΓD+→ρ0μ+νμ, the uncertainty is the quadratic sum of the statistical and systematic uncertainties.
By analyzing an e+e− annihilation data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, we measure the branching fraction of the D0→ρ−μ+νμ decay for the first time. We obtain BD0→ρ−μ+νμ=(1.35±0.09stat±0.09syst)×10−3. Combining with theoretical predictions, we extract the CKM matrix element |Vcd|=0.204±0.007stat±0.007syst±0.014theory. Using the world average of BD0→ρ−e+νe, we find a branching fraction ratio of BD0→ρ−μ+νμ/BD0→ρ−e+νe=0.90±0.11, which agrees with the theoretical expectation of lepton flavor universality within the uncertainty. Combining the world average of BD+→ρ0μ+νμ and the lifetimes of D0(+), we obtain a partial decay width ratio of ΓD0→ρ−μ+νμ/(2ΓD+→ρ0μ+νμ)=0.71±0.14, which is consistent with the isospin symmetry expectation of one within 2.1σ. For the reported values of BD0→ρ−μ+νμ/BD0→ρ−e+νe and ΓD0→ρ−μ+νμ/2ΓD+→ρ0μ+νμ, the uncertainty is the quadratic sum of the statistical and systematic uncertainties.