Multi-omics signatures in new-onset diabetes predict metabolic response to dietary inulin: findings from an observational study followed by an interventional trial

AIM: The metabolic performance of the gut microbiota contributes to the onset of type 2 diabetes. However, targeted dietary interventions are limited by the highly variable inter-individual response. We hypothesized (1) that the composition of the complex gut microbiome and metabolome (MIME) differ across metabolic spectra (lean-obese-diabetes); (2) that specific MIME patterns could explain the differential responses to dietary inulin; and (3) that the response can be predicted based on baseline MIME signature and clinical characteristics. METHOD: Forty-nine patients with newly diagnosed pre/diabetes (DM), 66 metabolically healthy overweight/obese (OB), and 32 healthy lean (LH) volunteers were compared in a cross-sectional case-control study integrating clinical variables, dietary intake, gut microbiome, and fecal/serum metabolomes (16 S rRNA sequencing, metabolomics profiling). Subsequently, 27 DM were recruited for a predictive study: 3 months of dietary inulin (10 g/day) intervention. RESULTS: MIME composition was different between groups. While the DM and LH groups represented opposite poles of the abundance spectrum, OB was closer to DM. Inulin supplementation was associated with an overall improvement in glycemic indices, though the response was very variable, with a shift in microbiome composition toward a more favorable profile and increased serum butyric and propionic acid concentrations. The improved glycemic outcomes of inulin treatment were dependent on better baseline glycemic status and variables related to the gut microbiota, including the abundance of certain bacterial taxa (i.e., Blautia, Eubacterium halii group, Lachnoclostridium, Ruminiclostridium, Dialister, or Phascolarctobacterium), serum concentrations of branched-chain amino acid derivatives and asparagine, and fecal concentrations of indole and several other volatile organic compounds. CONCLUSION: We demonstrated that obesity is a stronger determinant of different MIME patterns than impaired glucose metabolism. The large inter-individual variability in the metabolic effects of dietary inulin was explained by differences in baseline glycemic status and MIME signatures. These could be further validated to personalize nutritional interventions in patients with newly diagnosed diabetes

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Recommendation for the discrimination of human-related and natural seismicity

Various techniques are utilized by the seismological community, extractive industries, energy and geoengineering companies to identify earthquake nucleation processes in close proximity to engineering operation points. These operations may comprise fluid extraction or injections, artificial water reservoir impoundments, open pit and deep mining, deep geothermal power generations or carbon sequestration. In this letter to the editor, we outline several lines of investigation that we suggest to follow to address the discrimination problem between natural seismicity and seismic events induced or triggered by geoengineering activities. These suggestions have been developed by a group of experts during several meetings and workshops, and we feel that their publication as a summary report is helpful for the geoscientific community. Specific investigation procedures and discrimination approaches, on which our recommendations are based, are also published in this Special Issue (SI) of Journal of Seismology

Experimental access to Transition Distribution Amplitudes with the P̄ANDA experiment at FAIR

Baryon-to-meson Transition Distribution Amplitudes (TDAs) encoding valuable new information on hadron structure appear as building blocks in the collinear factorized description for several types of hard exclusive reactions. In this paper, we address the possibility of accessing nucleon-to-pion (\u3c0N) TDAs from \uafpp \u2192 e+e 12\u3c00 reaction with the future PANDA detector at the FAIR facility. At high center- of-mass energy and high invariant mass squared of the lepton pair q2, the amplitude of the signal channel pp\uaf \u2192 e+e 12\u3c00 admits a QCD factorized description in terms of \u3c0N TDAs and nucleon Distribution Amplitudes (DAs) in the forward and backward kinematic regimes. Assuming the validity of this factorized description, we perform feasibility studies for measuring \uafpp \u2192 e+e 12\u3c00 with the PANDA detector. Detailed simulations on signal reconstruction efficiency as well as on rejection of the most severe background channel, i.e. pp\uaf \u2192 \u3c0+\u3c0 12\u3c00 were performed for the center-of-mass energy squared s = 5 GeV2 and s = 10 GeV2, in the kinematic regions 3.0 0.5 in the proton-antiproton center-of-mass frame. Results of the simulation show that the particle identification capabilities of the PANDA detector will allow to achieve a background rejection factor of 5 \ub7 107 (1 \ub7 107) at low (high) q2 for s = 5 GeV2, and of 1 \ub7 108 (6 \ub7 106) at low (high) q2 for s = 10 GeV2, while keeping the signal reconstruction efficiency at around 40%. At both energies, a clean lepton signal can be reconstructed with the expected statistics corresponding to 2 fb 121 of integrated luminosity. The cross sections obtained from the simulations are used to show that a test of QCD collinear factorization can be done at the lowest order by measuring scaling laws and angular distributions. The future measurement of the signal channel cross section with PANDA will provide a new test of the perturbative QCD description of a novel class of hard exclusive reactions and will open the possibility of experimentally accessing \u3c0N TDAs

Technical design report for the P‾ANDA\overline{{\rm{P}}}\mathrm{ANDA} Barrel DIRC detector

The $\overline{{\rm{P}}}\mathrm{ANDA}$ (anti-Proton ANnihiliation at DArmstadt) experiment will be one of the four flagship experiments at the new international accelerator complex FAIR (Facility for Antiproton and Ion Research) in Darmstadt, Germany. $\overline{{\rm{P}}}\mathrm{ANDA}$ will address fundamental questions of hadron physics and quantum chromodynamics using high-intensity cooled antiproton beams with momenta between 1.5 and 15 GeV/c and a design luminosity of up to 2 × 1032 cm−2 s−1. Excellent particle identification (PID) is crucial to the success of the $\overline{{\rm{P}}}\mathrm{ANDA}$ physics program. Hadronic PID in the barrel region of the target spectrometer will be performed by a fast and compact Cherenkov counter using the detection of internally reflected Cherenkov light (DIRC) technology. It is designed to cover the polar angle range from 22° to 140° and will provide at least 3 standard deviations (s.d.) π/K separation up to 3.5 GeV/c, matching the expected upper limit of the final state kaon momentum distribution from simulation. This documents describes the technical design and the expected performance of the $\overline{{\rm{P}}}\mathrm{ANDA}$ Barrel DIRC detector. The design is based on the successful BaBar DIRC with several key improvements. The performance and system cost were optimized in detailed detector simulations and validated with full system prototypes using particle beams at GSI and CERN. The final design meets or exceeds the PID goal of clean π/K separation with at least 3 s.d. over the entire phase space of charged kaons in the Barrel DIRC

Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

BACKGROUND: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy