Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

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

Entrepreneurial Human Capital, Complementary Assets, and Takeover Probability

Gaining access to technologies, competencies, and knowledge is observed as one of the major motives for corporate mergers and acquisitions. In this paper we show that a knowledge-based firm's probability of being a takeover target is influenced by whether relevant specific human capital aimed for in acquisitions is directly accumulated within a specific firm or is bound to its founder or manager owner. We analyze the incentive effects of different arrangements of ownership in a firm's assets in the spirit of the Grossman-Hart-Moore incomplete contracts theory of the firm. This approach highlights the organizational significance of ownership of complementary assets. In a small theoretical model we assume that the entrepreneur's specific human capital, as measured by the patents they own, and the physical assets of their firm are productive only when used together. Our results show that it is not worthwhile for an acquirer to purchase the alienable assets of this firm due to weakened incentives for the initial owner. Regression analysis using a hand collected dataset of all German IPOs in the period from 1997 to 2006 subsequently provides empirical support for this prediction. This paper adds to previous research in that it puts empirical evidence to the Grossman-Hart-Moore framework of incomplete contracts or property rights respectively. Secondly, we show that relevant specific human capital that is accumulated by a firm's founder or manager owner significantly decreases that firm's probability of being a takeover target

Performance of the new seedless grape ‘BRS Isis' grown in subtropical area

‘BRS Isis' is a new colored seedless table grape tolerant to downy mildew, the main vine disease in subtropical humid areas. This new seedless cultivar is an interspecific hybrid from the crossing of CNPUV 681–29 [Arkansas 1976 X CNPUV 147–3 (‘Niagara Branca' x ‘Venus')] x ‘BRS Linda', and was recently released by Embrapa Grape and Wine, Brazil. The performance of ‘BRS Isis' seedless grape was evaluated in an experimental vineyard in 2016 located in a subtropical area at Marialva city, state of Parana, Brazil. The vines were grafted onto ‘IAC 766 Campinas' rootstock and trained in an overhead trellising system spaced at 2× 5 m. Vines were cane-pruning in late winter of July 2016, and for assessments, 20 representative vines were selected in the area. As ‘BRS Isis' is a very fruitful grape, presenting 4 bunches per shoot, a load adjustment was performed after fruitset removing 50% of bunches per shoot, leaving 2 bunches per shoot, equivalent to a density of 10 bunches.m−2. The duration in days of the main phenological stages from pruning to harvest, and the physicochemical and yield characteristics of ‘BRS Isis' seedless grape were subjected to evaluation. It was determined that the cycle is 144 days. The means of berry and bunch weight was 6.7 ± 1.0 g and 500.0 ± 0.04 g, respectively, and the color index of berries (CIRG) was 4.3 ± 1.3. The means of total soluble solids (TSS), titratable acidity (TA) and maturity index (TSS/TA) observed were 14.2 ± 0.3° Brix, 0.6 ± 0.04% of tartaric acid and 24.1 ± 1.5, respectively, while the yield was 49.0 ± 5.7 tons.ha−1. The yield observed is considered high to keep a sustainable crop over time, thus, in order to obtain grapes of ‘BRS Isis' with regular yield, and possibly, with a higher content of soluble solids, it is desirable to keep only 1 bunch per shoot (5 bunches.m−2) after fruitset

Performance of the new seedless grape ‘BRS Isis' grown in subtropical area

‘BRS Isis' is a new colored seedless table grape tolerant to downy mildew, the main vine disease in subtropical humid areas. This new seedless cultivar is an interspecific hybrid from the crossing of CNPUV 681–29 [Arkansas 1976 X CNPUV 147–3 (‘Niagara Branca' x ‘Venus')] x ‘BRS Linda', and was recently released by Embrapa Grape and Wine, Brazil. The performance of ‘BRS Isis' seedless grape was evaluated in an experimental vineyard in 2016 located in a subtropical area at Marialva city, state of Parana, Brazil. The vines were grafted onto ‘IAC 766 Campinas' rootstock and trained in an overhead trellising system spaced at 2× 5 m. Vines were cane-pruning in late winter of July 2016, and for assessments, 20 representative vines were selected in the area. As ‘BRS Isis' is a very fruitful grape, presenting 4 bunches per shoot, a load adjustment was performed after fruitset removing 50% of bunches per shoot, leaving 2 bunches per shoot, equivalent to a density of 10 bunches.m−2. The duration in days of the main phenological stages from pruning to harvest, and the physicochemical and yield characteristics of ‘BRS Isis' seedless grape were subjected to evaluation. It was determined that the cycle is 144 days. The means of berry and bunch weight was 6.7 ± 1.0 g and 500.0 ± 0.04 g, respectively, and the color index of berries (CIRG) was 4.3 ± 1.3. The means of total soluble solids (TSS), titratable acidity (TA) and maturity index (TSS/TA) observed were 14.2 ± 0.3° Brix, 0.6 ± 0.04% of tartaric acid and 24.1 ± 1.5, respectively, while the yield was 49.0 ± 5.7 tons.ha−1. The yield observed is considered high to keep a sustainable crop over time, thus, in order to obtain grapes of ‘BRS Isis' with regular yield, and possibly, with a higher content of soluble solids, it is desirable to keep only 1 bunch per shoot (5 bunches.m−2) after fruitset

Optimizing the extraction of anthocyanins from the skin and phenolic compounds from the seed of jabuticaba fruits (Myrciaria jabuticaba (Vell.) O. Berg) with ternary mixture experimental designs

Total phenolic compounds (TPC) extraction from the seed and total monomeric anthocyanins (TMA) extraction from the skin of "Sabara" jabuticaba were optimized with simplex lattice designs for solvent mixing, and the extraction time was optimized by univariate design. The optimum conditions for the extraction method were ethanol: water (60: 40 v/v) solvent for TPC (seed) and methanol: water: acetic acid (80:20:0.5 v/v/v) solvent for TMA (skin). For both compound groups, the optimum extraction time was 30 min. The TMA yield for the skin of the "Sabara" variety was 1172.16 mg cyanidin-3-glycoside equivalents per 100 g freeze-dried sample, and for TPC in the seed, it was 86.50 mg gallic acid equivalents per 1 g freeze-dried sample. Both optimized extraction protocols proved to be extremely fast, simple, inexpensive and to have excellent extraction performance. The optimized protocols were compared with two other methods described in the literature and they were also applied to study the TMA contents in skin and the TPC contents in seed of five other varieties of jabuticaba, harvested in 2014 and 201530715061514CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ145652/2014-