An Experimental DUAL Model of Advanced Liver Damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.Supported by EXOHEP-CM (S2017/BMD-3727), Ramón y Cajal (RYC-2014-15242 and RYC-2015-17438), NanoLiver-CM (Y2018/NMT-4949), COST Action (CA17112), AMMF (2018/117), ERAB (EA 18/14), MINECO Retos (SAF2016-78711 and SAF2017-87919-R), and German Research Foundation (DFG NE 2128/2-1, SFB 1382-403224013/A02, and SFB/TRR57/P04). FJC is a Gilead Research Liver Scholar. The research group belongs to the validated Research group Ref. 970935 “Liver Pathophysiology”, 920631 “Lymphocyte immunology”, 920361 “Immunogenética e inmunología de las mucosas” and IBL-6 (imas12-associated). FG and KZ are Chinese Scholarship Council (CSC) fellows. O.E.-V is supported by Beca FPI (associated to MINECO SAF2017-87919R) and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19)

An experimental DUAL model of advanced liver damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets

Surgical outcomes in the pheochromocytoma surgery. Results from the PHEO-RISK STUDY.

To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery. A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale. One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P  Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort : 2004-2013

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS. Of 7165 new HIV diagnoses, 46.9% (CI:45.7-48.0) were LP, 240 patients died.First-year mortality was the highest (aHR = 10.3[CI:5.5-19.3]); between 1 and 4 years post-diagnosis, aHR = 1.9(1.2-3.0); an

Observation of the Λb0→χc1(3872)pK−\Lambda_b^0\rightarrow \chi_{c1}(3872)pK^- decay

International audienceUsing proton-proton collision data, collected with the LHCb detector and corresponding to 1.0, 2.0 and 1.9 fb$^{−1}$ of integrated luminosity at the centre-of-mass energies of 7, 8, and 13 TeV, respectively, the decay {\Lambda}_{\mathrm{b}}^0\to {\upchi}_{\mathrm{c}1} (3872)pK$^{−}$ with χ$_{c1}$(3872) → J/ψ π$^{+}$π$^{−}$ is observed for the first time. The significance of the observed signal is in excess of seven standard deviations. It is found that (58 ± 15)% of the decays proceed via the two-body intermediate state χ$_{c1}$(3872)Λ(1520). The branching fraction with respect to that of the ${\Lambda}_{\mathrm{b}}^0$ → ψ(2S)pK$^{−}$ decay mode, where the ψ(2S) meson is reconstructed in the J/ψ π$^{+}$π$^{−}$ final state, is measured to be: $ \frac{\beta \left({\Lambda}_{\mathrm{b}}^0\to {\upchi}_{\mathrm{c}1}(3872){\mathrm{pK}}^{-}\right)}{\beta \left({\Lambda}_{\mathrm{b}}^0\to \uppsi \left(2\mathrm{S}\right){\mathrm{pK}}^{-}\right)}\times \frac{\beta \left({\upchi}_{\mathrm{c}1}(3872)\to \mathrm{J}/\uppsi {\uppi}^{+}{\uppi}^{-}\right)}{\beta \left(\uppsi \left(2\mathrm{S}\right)\to \mathrm{J}/\uppsi {\uppi}^{+}{\uppi}^{-}\right)}=\left(5.4\pm 1.1\pm 0.2\right)\times {10}^{-2},

Measurement of fs/fuf_s / f_u Variation with Proton-Proton Collision Energy and BB-Meson Kinematics

International audienceThe ratio of the Bs0 and B+ fragmentation fractions fs and fu is studied with Bs0→J/ψϕ and B+→J/ψK+ decays using data collected by the LHCb experiment in proton-proton collisions at 7, 8, and 13 TeV center-of-mass energies. The analysis is performed in bins of B-meson momentum, longitudinal momentum, transverse momentum, pseudorapidity, and rapidity. The fragmentation-fraction ratio fs/fu is observed to depend on the B-meson transverse momentum with a significance of 6.0σ. This dependency is driven by the 13 TeV sample (8.7σ), while the results for the other collision energies are not significant when considered separately. Furthermore, the results show a 4.8σ evidence for an increase of fs/fu as a function of collision energy

Measurement of the branching fraction of the decay Bs0→KS0KS0B_s^0\to K_S^0 K_S^0

International audienceA measurement of the branching fraction of the decay Bs0→KS0KS0 is performed using proton–proton collision data corresponding to an integrated luminosity of 5  fb-1 collected by the LHCb experiment between 2011 and 2016. The branching fraction is determined to be B(Bs0→KS0KS0)=[8.3±1.6(stat)±0.9(syst)±0.8(norm)±0.3(fs/fd)]×10-6, where the first uncertainty is statistical, the second is systematic, and the third and fourth are due to uncertainties on the branching fraction of the normalization mode B0→ϕKS0 and the ratio of hadronization fractions fs/fd. This is the most precise measurement of this branching fraction to date. Furthermore, a measurement of the branching fraction of the decay B0→KS0KS0 is performed relative to that of the Bs0→KS0KS0 channel, and is found to be B(B0→KS0KS0)B(Bs0→KS0KS0)=[7.5±3.1(stat)±0.5(syst)±0.3(fs/fd)]×10-2