Lattice Spacing Dependence of the First Order Phase Transition for Dynamical Twisted Mass Fermions

Lattice QCD with Wilson fermions generically shows the phenomenon of a first order phase transition. We study the phase structure of lattice QCD using Wilson twisted mass fermions and the Wilson plaquette gauge action are used in a range of beta values where such a first order phase transition is observed. In particular, we investigate the dependence of the first order phase transition on the value of the lattice spacing. Using only data in one phase and neglecting possible problems arising from the phase transition we are able to perform a first scaling test for physical quantities using this action.Comment: 15 pages, 7 figures, typo corrected, web-list of authors correcte

Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss

Context: Obesity and type 2 diabetes mellitus are associated with increased levels of IL-6, a marker of inflammation. Objective: This study addressed the question of whether IL-6 was released from skeletal muscle after a high-fat meal in men with impaired glucose tolerance (IGT), a prediabetic state, and whether IL-6 release could be reduced by weight loss. Design: Skeletal muscle metabolism was studied in men with IGT (n = 11) and compared with men with normal glucose tolerance (NGT, n = 9), matched for body mass index and age. IL-6 flux over skeletal muscle was measured with the forearm model. Eight IGT men were willing to participate in a 12-wk weight loss program and were tested again. Results: IL-6, but not C-reactive protein or TNF- receptor 1 and 2, was released by skeletal muscle. Muscle IL-6 release was higher in IGT than in NGT during fasting (IGT = 2.26 ± 1.89 vs. NGT = 0.87 ± 0.48 fmol*100 ml tissue¿1*min¿1, P = 0.04) and after a meal (mean area under the curve per minute: IGT = 3.48 ± 2.63 vs. NGT = 1.37 ± 0.75 fmol*100 ml tissue¿1*min¿1; P = 0.03). In the IGT men, body weight loss resulted in a decrease of postprandial IL-6 release from skeletal muscle (¿52%; P = 0.04), reaching levels of the obese, NGT controls. Conclusion: The present data suggest that a high-fat meal can evoke IL-6 release from muscle and that the IL-6 release is a consequence rather than a cause of the obese, insulin-resistant, and/or IGT state

Cytogenetic characterization of telomeres in the holocentric chromosomes of the lepidopteran Mamestra brassicae

Telomeres of the Mamestra brassica holocentric chromosomes were studied by Southern blotting, in-situ hybridization and Bal31 assay evidencing the presence of the telomeric (TTAGG)(n) repeat. Successively, molecular analysis of telomeres showed that TRAS1 transposable elements were present at the subtelomeric regions of autosomes but not in the NOR-bearing telomeres of the Z and W sex chromosomes. TRAS1 appeared to be transcriptionally active and non-methylated, as evaluated by RT-PCR and digestion with MspI and HpaII. Finally, dot-blotting experiments showed that the 2.8 +/- 0.5% of the M. brassicae genome consists of TRAS1

Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients:First data from the TITRATE-HF study

Aims: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. Methods and results: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63–78), 29% were female, and median ejection fraction was 35% (IQR 25–40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. Conclusion: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.</p

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.Experimentele farmacotherapi

An updated evaluation of the implementation of the sigmoid take-off landmark 1 year after the official introduction in the Netherlands

PURPOSE: The definition of rectal cancer based on the sigmoid take-off (STO) was incorporated into the Dutch guideline in 2019, and became mandatory in the national audit from December 2020. This study aimed to evaluate the use of the STO in clinical practice and the added value of online training, stratified for the period before (group A, historical cohort) and after (group B, current cohort) incorporation into the national audit.METHODS: Participants, including radiologists, surgeons, surgical and radiological residents, interns, PhD students, and physician assistants, were asked to complete an online training program, consisting of questionnaires, 20 MRI cases, and a training document. Outcomes were agreement with the expert reference, inter-rater variability, and accuracy before and after the training.RESULTS: Group A consisted of 86 participants and group B consisted of 114 participants. Familiarity with the STO was higher in group B (76% vs 88%, p = 0.027). Its use in multidisciplinary meetings was not significantly higher (50% vs 67%, p = 0.237). Agreement with the expert reference was similar for both groups before (79% vs 80%, p = 0.423) and after the training (87% vs 87%, p = 0.848). Training resulted in significant improvement for both groups in classifying tumors located around the STO (group A, 69-79%; group B, 67-79%, p &lt; 0.001).CONCLUSIONS: The results of this study show that after the inclusion of the STO in the mandatory Dutch national audit, the STO was consequently used in only 67% of the represented hospitals. Online training has the potential to improve implementation and unambiguous assessment.</p