Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus

The benefit or risk of sodium glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus has not been established. We aimed to assess the comparative CV safety and mortality risk associated with the use of SGLT2 inhibitors. PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were systematically searched up to January 27, 2016, to identify randomized controlled trials (RCTs) with the use of SGLT2 inhibitors of at least 24 weeks of duration. The primary outcomes included all-cause mortality and major adverse cardiovascular events. A random-effects network meta-analysis was performed to calculate the odds ratio (OR) with 95% CI. We identified 37 eligible trials involving 29,859 patients that compared 3 SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to placebo and other active antidiabetic treatments. Of all direct and indirect comparisons, only empagliflozin compared with placebo was significantly associated with lower risk of all-cause mortality (OR 0.67, 95% CI 0.56 to 0.81) and major adverse cardiovascular events (OR 0.81, 95% CI 0.70 to 0.93). However, the significant effect of empagliflozin was largely driven by one large randomized trial (EMPA-REG OUTCOME trial). Neither dapagliflozin nor canagliflozin was significantly associated with any harm. In conclusion, current RCT evidence suggests that 3 common SGLT2 inhibitors are not associated with increased risk of all-cause mortality and CV outcomes when used to treat patients with type 2 diabetes mellitus. Although empagliflozin may have a protective effect, further confirmative data from rigorous RCTs are needed

The causal relationship between genetically determined telomere length and meningiomas risk

BackgroundStudies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors.MethodsWe used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR).ResultsIn the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10−5], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected.ConclusionIn brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations

Safety and tolerability of a single dose T0001 in Chinese healthy adult volunteers: a first-in-human ascending dose study

T0001 is the first mutant of etanercept with a higher affinity to tumor necrosis factor α (TNF-α) than etanercept. In order to investigate the safety and tolerability of T0001, a study was carried out in healthy Chinese subjects. A first-in-human, dose escalation study was conducted in healthy Chinese subjects. Fifty-six subjects were divided into six dose cohorts (10 mg, 20 mg, 35 mg, 50 mg, 65 mg and 75 mg) to receive a single subcutaneous injection of T0001. Safety and tolerability assessment were based on the records of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms and adverse events (AEs). All subjects were in good compliance and none withdraw due to AEs. No serious AEs occurred. A total of twenty-three AEs in sixteen subjects were recorded, and eighteen of these AEs were believed to be related to T0001. The most frequently reported AEs were injection site reactions and white blood cell count increase. All these AEs were of mild to moderate intensity and most of them recovered spontaneously within 14 days. In this study, no dose-limiting toxicity was observed, and the maximum tolerated dose was identified as 75 mg. T0001 was considered safe and generally well tolerated at doses up to 75 mg in healthy Chinese volunteers

Application of the pressure cooker technique for transarterial embolization of brain arteriovenous malformations: Factors affecting obliteration and outcomes

ObjectiveThe typical pressure cooker technique (PCT) and several modifications with similar mechanisms have been introduced to enhance the embolization of brain arteriovenous malformations (bAVMs). This study aimed to assess the effectiveness of transarterial embolization of bAVMs with the PCT.MethodFrom January 2019 to December 2021, 125 consecutive patients with bAVM managed by transarterial embolization in the prospective database on cerebral vascular diseases of a single center were retrospectively reviewed. Patient data and lesion characteristics were collected. According to the treatment strategy, the patients were assigned to the PCT group (46 patients) and conventional embolization technique (CET) group (79 patients).ResultsBaseline patient features were comparable between the two groups. After the first procedure, complete obliteration immediately was observed in 61 and 42% of patients in the PCT and CET groups, respectively. The rate was markedly elevated in the PCT group (p = 0.04). In subgroup analysis, the rate of immediate complete obliteration was starkly increased in PCT group patients with Spetzler-Martin grade I/II bAVM (86 and 53% in the PCT and CET groups, respectively; p = 0.0036). The overall complication rates were similar in the two groups (13 and 10% in the PCT and CET groups, respectively; p = 0.77). In multivariable analysis, nidus size >3 cm (OR = 8.826, 95% CI: 1.250–62.312; p = 0.03) and deep location (OR = 8.576, 95% CI: 1.480–49.690; p = 0.02) were significant factors affecting complete obliteration in the PCT group.ConclusionThe PCT may yield a higher rate of immediate complete obliteration with transarterial embolization of bAVMs, without increasing the rate of procedure-related complications

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Precision Higgs physics at the CEPC

The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics. The Higgs boson will be the subject of extensive studies of the ongoing LHC program. At the same time, lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC, with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson. The Circular Electron Positron Collider~(CEPC) is one of such proposed Higgs factories. The CEPC is an $e^+e^-$ circular collider proposed by and to be hosted in China. Located in a tunnel of approximately 100~km in circumference, it will operate at a center-of-mass energy of 240~GeV as the Higgs factory. In this paper, we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.Comment: 46 pages, 37 figure