A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

Dynamics of viscoelastic membranes

We determine both the in-plane and out-of-plane dynamics of viscoelastic membranes separating two viscous fluids in order to understand microrheological studies of such membranes. We demonstrate the general viscoelastic signatures in the dynamics of shear, bending, and compression modes. We also find a screening of the otherwise two-dimensional character of the response to point forces due to the presence of solvent. Finally, we show that there is a linear, hydrodynamic coupling between the in-plane compression modes of the membrane and the out-of-plane bending modes in the case where the membrane separates two different fluids or environments

Mechanical robustness of HL-LHC collimator designs

Two new absorbing materials were developed as collimator inserts to fulfil the requirements of HL-LHC higher brightness beams: molybdenum-carbide graphite (MoGr) and copper-diamond (CuCD). These materials were tested under intense beam impacts at CERN HiRadMat facility in 2015, when full jaw prototypes were irradiated. Additional tests in HiRadMat were performed in 2017 on another series of material samples, including also improved grades of MoGr and CuCD, and different coating solutions. This paper summarizes the main results of the two experiments, with a main focus on the behaviour of the novel composite blocks, the metallic housing, as well as the cooling circuit. The experimental campaign confirmed the final choice for the materials and the design solutions for HL-LHC collimators, and constituted a unique chance of benchmarking numerical models. In particular, the tests validated the selection of MoGr for primary and secondary collimators, and CuCD as a valid solution for robust tertiary collimators

Wetland succession in a permafrost collapse: interactions between fire and thermokarst

To determine the influence of fire and thermokarst in a boreal landscape, we investigated peat cores within and adjacent to a permafrost collapse feature on the Tanana River Floodplain of Interior Alaska. Radioisotope dating, diatom assemblages, plant macrofossils, charcoal fragments, and carbon and nitrogen content of the peat profile indicate ~600 years of vegetation succession with a transition from a terrestrial forest to a sedge-dominated wetland over 100 years ago, and to a <i>Sphagnum</i>-dominated peatland in approximately 1970. The shift from sedge to <i>Sphagnum</i>, and a decrease in the detrended tree-ring width index of black spruce trees adjacent to the collapse coincided with an increase in the growing season temperature record from Fairbanks. This concurrent wetland succession and reduced growth of black spruce trees indicates a step-wise ecosystem-level response to a change in regional climate. In 2001, fire was observed coincident with permafrost collapse and resulted in lateral expansion of the peatland. These observations and the peat profile suggest that future warming and/or increased fire disturbance could promote permafrost degradation, peatland expansion, and increase carbon storage across this landscape; however, the development of drought conditions could reduce the success of both black spruce and <i>Sphagnum</i>, and potentially decrease the long-term ecosystem carbon storage

Self-dual Ginzburg-Landau vortices in a disk

We study the properties of the Ginzburg-Laundau model in the self-dual point for a two-dimensional finite system . By a numerical calculation we analyze the solutions of the Euler-Lagrange equations for a cylindrically symmetric ansatz. We also study the self-dual equations for this case. We find that the minimal energy configurations are not given by the Bogomol'nyi equations but by solutions to the Euler Lagrange ones. With a simple approximation scheme we reproduce the result of the numerical calculation.Comment: 8 pages, 4 figures, RevTex macro

Project20: Maternity care mechanisms that improve (or exacerbate) health inequalities. A realist evaluation

Background Women with low socioeconomic status and social risk factors are at a disproportionate risk of poor birth outcomes and experiences of maternity care. Specialist models of maternity care that offer continuity are known to improve outcomes but underlying mechanisms are not well understood. Aim To evaluate two UK specialist models of care that provide continuity to women with social risk factors and identify specific mechanisms that reduce, or exacerbate, health inequalities. Methods Realist informed interviews were undertaken throughout pregnancy and the postnatal period with 20 women with social risk factors who experienced a specialist model of care. Findings Experiences of stigma, discrimination and paternalistic care were reported when women were not in the presence of a known midwife during care episodes. Practical and emotional support, and evidence-based information offered by a known midwife improved disclosure of social risk factors, eased perceptions of surveillance and enabled active participation. Continuity of care offered reduced women’s anxiety, enabled the development of a supportive network and improved women’s ability to seek timely help. Women described how specialist model midwives knew their medical and social history and how this improved safety. Care set in the community by a team of six known midwives appeared to enhance these benefits. Conclusion The identification of specific maternity care mechanisms supports current policy initiatives to scale up continuity models and will be useful in future evaluation of services for marginalised groups. However, the specialist models of care cannot overcome all inequalities without improvements in the maternity system as a whole

Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism

Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population

The selection of search sources influences the findings of a systematic review of people’s views: a case study in public health

Background For systematic reviews providing evidence for policy decisions in specific geographical regions, there is a need to minimise regional bias when seeking out relevant research studies. Studies on people’s views tend to be dispersed across a range of bibliographic databases and other search sources. It is recognised that a comprehensive literature search can provide unique evidence not found from a focused search; however, the geographical focus of databases as a potential source of bias on the findings of a research review is less clear. This case study describes search source selection for research about people’s views and how supplementary searches designed to redress geographical bias influenced the findings of a systematic review. Our research questions are: a) what was the impact of search methods employed to redress potential database selection bias on the overall findings of the review? and b) how did each search source contribute to the identification of all the research studies included in the review? Methods The contribution of 25 search sources in locating 28 studies included within a systematic review on UK children’s views of body size, shape and weight was analysed retrospectively. The impact of utilising seven search sources chosen to identify UK-based literature on the review’s findings was assessed. Results Over a sixth (5 out of 28) of the studies were located only through supplementary searches of three sources. These five studies were of a disproportionally high quality compared with the other studies in the review. The retrieval of these studies added direction, detail and strength to the overall findings of the review. All studies in the review were located within 21 search sources. Precision for 21 sources ranged from 0.21% to 1.64%. Conclusions For reducing geographical bias and increasing the coverage and context-specificity of systematic reviews of people’s perspectives and experiences, searching that is sensitive and aimed at reducing geographical bias in database sources is recommended

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults with Focal Epilepsy A Phase 2b Randomized Clinical Trial

IMPORTANCE Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. OBJECTIVE To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). DESIGN, SETTING, AND PARTICIPANTS This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. INTERVENTIONS Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). MAIN OUTCOMES AND MEASURES The primary efficacy end pointwas the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. RESULTS A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8%(P < .001 vs placebo; IQR, -80.4%to -16.9%) for 25mg, 46.4% (P < .001 vs placebo; IQR, -76.7%to -14.0%) for 20mg, and 33.2%(P = .04 vs placebo; IQR, -61.8%to 0.0%) for 10mg, compared with 18.2%(IQR, -37.3%to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. CONCLUSIONS AND RELEVANCE The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs

Faraday waves on a viscoelastic liquid

We investigate Faraday waves on a viscoelastic liquid. Onset measurements and a nonlinear phase diagram for the selected patterns are presented. By virtue of the elasticity of the material a surface resonance synchronous to the external drive competes with the usual subharmonic Faraday instability. Close to the bicriticality the nonlinear wave interaction gives rise to a variety of novel surface states: Localised patches of hexagons, hexagonal superlattices, coexistence of hexagons and lines. Theoretical stability calculations and qualitative resonance arguments support the experimental observations.Comment: 4 pages, 4figure