Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort.

Abstract Background and aims. Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. Methods. Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. Results. Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. Conclusion. Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Transposition of great arteries and single coronary artery: a new surgical technique for the arterial switch operation.

A single coronary artery can complicate the surgical technique of arterial switch operations, impairing early and late outcomes. We propose a new surgical approach, successfully applied in a 2.1 kg neonate, aimed at reducing the risk of early and late compression and/or distortion of the newly constructed coronary artery system.

A wearable system to time gate crossing during alpine skiing slalom

INTRODUCTION: In alpine skiing, chronometry analysis is currently the most common tool to assess performance. It is widely used to rank competitors during races, as well as to manage athletes training and to evaluate material. Usually, this measurement is accurately realized using timing cells. Nevertheless, these devices are too complex and expensive to allow chronometry of every gates crossing. On the other side, differential GPS can be used for measuring gate crossing time (Waegli et al). However, this is complex (e.g. recording gate position with GPS) and mainly used in research applications. The aim of the study was to propose a wearable system to time gates crossing during alpine skiing slalom (SL), which is suitable for routine uses. METHODS: The proposed system was composed of a 3D accelerometer (ADXL320®, Analog Device, USA) placed at the sacrum of the athlete, a matrix of force sensors (Flexiforce®, Tekscan, USA) fixed on the right shin guard and a data logger (Physilog®, BioAGM, Switzerland). The sensors were sampled at 500 Hz. The crossing time were calculated in two phases. First, the accelerometer was used to detect the curves by considering the maximum of the mediolateral peak acceleration. Then, the force sensors were used to detect the impacts with the gates by considering maximum force variation. In case of non impact, the detection was realized based on the acceleration and features measured at the other gates. In order to assess the efficiency of the system, two different SL were monitored twice for two world cup level skiers, a male SL expert and a female downhill expert. RESULTS AND DISCUSSION: The combination of the accelerometer and force sensors allowed to clearly identify the gate crossing times. When comparing the runs of the SL expert and the downhill expert, we noticed that the SL expert was faster. For example for the first SL, the overall difference between the best run of each athlete was of 5.47s. At each gate, the SL expert increased the time difference slower at the beginning (0.27s/gate) than at the end (0.34s/gate). Furthermore, when comparing the runs of the SL expert, a maximum time difference of 20ms at each gate was noticed. This showed high repeatability skills of the SL expert. In opposite, the downhill expert with a maximum difference time of 1s at each gate was clearly less repeatable. Both skiers were not disturbed by the system. CONCLUSION: This study proposed a new wearable system to automatically time gates crossing during alpine skiing slalom combining force and accelerometer sensors. The system was evaluated with two professional world cup skiers and showed a high potential. This system could be extended to time other parameters. REFERENCES Waegli A, Skaloud J (2007). Inside GNSS, Spring, 24-34.

Dramatic response of vemurafenib-induced cutaneous lesions upon switch to dual BRAF/MEK inhibition in a metastatic melanoma patient.

BRAF inhibitory therapy is the mainstream treatment for BRAF mutant advanced melanoma. However vemurafenib, a type I mutant BRAF V600 inhibitor, induces an array of proliferative skin disorders from keratosis pilaris-like and keratoacanthoma-like lesions to locally aggressive cutaneous squamous cell carcinoma (cuSCC). Dual BRAF/MEK inhibition is known to lower the incidence of such manifestations, but it is not known whether it can counteract established lesions. Here we show, for the first time, a dramatic response and a restitution ad integro upon dual inhibition of a widespread proliferative affection induced by BRAF monotherapy. A 75-year-old woman was diagnosed with a BRAF V600E mutated metastatic melanoma. Following dacarbazine (DTIC) and ipilimumab, the patient was started on 960 mg twice daily vemurafenib (Zelboraf), which resulted in complete response, but the patient also developed grade IV skin toxicity. Despite dose-reduction to 720 mg twice daily the side effects persisted. We hypothesized that a switch to double inhibition of the mitogen-activated protein kinase pathway with dabrafenib and trametinib could lead to improvement of the skin lesions, while preserving tumor control. The patient was closely followed for changes in skin lesions. We witnessed a rapid regression followed by complete disappearance of all side effects of vemurafenib except for grade I fatigue. The biopsied skin lesions show regression of established keratoacanthoma-like lesions with signs of apoptosis. Switching from the current standard of care vemurafenib therapy to the double BRAF/MEK inhibition in BRAF mutant melanoma patients results in rapid disappearance of established proliferative skin disorders.

Switch to etravirine for HIV-positive patients receiving statin treatment: a prospective study.

BACKGROUND: Lifestyle changes and statins are the cornerstones in management of dyslipidaemia in patients with HIV infection. Replacement of an antiretroviral therapy (ART) component is a proposed therapeutic strategy to reduce cardiovascular risk. In dyslipidaemic patients with HIV infection, we assessed the efficacy of replacing boosted protease inhibitor (bPI) or efavirenz (EFV) by etravirine (ETR) as an alternative to statin therapy. MATERIALS AND METHODS: A prospective, open-label, multicentre, 12-week study of patients with HIV infection on ART including bPI or EFV, and statin treatment. Four weeks after statin interruption, bPI or EFV was switched to ETR (400 mg, 8 weeks) if serum low-density lipoprotein cholesterol (LDL-C) was ≥ 3 mM. The primary endpoint was the proportion of patients on ETR with no indication for statin treatment at study completion. Serum levels of HIV RNA, lipids and biomarkers of cardiovascular disease were also measured. (ClinicalTrials.gov: NCT01543035). RESULTS: The 31 included patients had a HIV-1 RNA < 50 copies/mL (median age, 52 years; median CD4, 709 cell/mL; median LDL-C, 2·89 mM), 68% were on EFV, and 32% were on bPI. At week 4, 27 patients switched to ETR. At study completion, 15 patients (56%) on ETR did not qualify for statin treatment. After the ETR switch, serum levels of the cardiovascular biomarkers sICAM and MCP1/CCL2 decreased by 11·2% and 18·9%, respectively, and those of CCL5/RANTES and tissue inhibitor of metalloproteinase-1 increased by 14·3% and 13·4%, respectively, indicating reduced cardiovascular risk. There were no notable treatment-related adverse events. CONCLUSIONS: Replacing bPI or EFV by ETR is a viable strategy to obviate primary prevention statin treatment.

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.

BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.