Model for coiling and meandering instability of viscous threads

A numerical model is presented to describe both the transient and steady-state dynamics of viscous threads falling onto a plane. The steady-state coiling frequency w is calculated as a function of fall height H. In the case of weak gravity, w ~ H^{-1} and w ~ H are obtained for lower and higher fall heights respectively. When the effect of gravity is significant, the relation w ~ H^2 is observed. These results agree with the scaling laws previously predicted. The critical Reynolds number for coil-uncoil transition is discussed. When the gravity is weak, the transition occurs with hysteresis effects. If the plane moves horizontally at a constant speed, a variety of meandering oscillation modes can be observed experimentally. The present model also can describe this phenomenon. The numerically obtained state diagram for the meandering modes qualitatively agrees with the experiment.Comment: 12 pages, 10 figure

Greenhouse gas considerations in rail infrastructure in the UK

Transportation-related greenhouse gas (GHG) emissions account for an increasing proportion of total emissions in the UK and globally. The provision of rail transit is popularly proposed to reduce transport GHG emissions, but the provision of new infrastructure is itself GHG intensive. Understanding of the GHG emissions impact of rail projects is limited and very few longitudinal studies have been carried out. Existing assessments are often limited both in their scope and the factors considered. A holistic understanding of GHG impacts must include an assessment of capital GHG emissions, operational energy and maintenance as well as an assessment of ridership mode shift and mode share impacts and the relationship between transit infrastructure and land use. This paper explores rail infrastructure projects and their associated GHG emissions. Guidance is given on the aspects of rail planning, design and construction that must be considered to more fully understand the associated GHG impacts.The authors would like to thank The Commonwealth Scholarship Commission in the UK for the scholarship funding that facilitated this work

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours--evaluation of a potentially effective clinical therapy.

Primary tumours of the central nervous system (CNS) are an important cause of cancer-related deaths in adults and children. CNS tumours are mostly glial cell in origin and are predominantly astrocytomas. Conventional therapy of high-grade gliomas includes maximal resection followed by radiation treatment. The addition of adjuvant chemotherapy provides little improvement in survival time and hence assessment of novel therapies is imperative. We have evaluated the potential therapeutic use of the herpes simplex virus (HSV) mutant 1716 in the treatment of primary brain tumours. The mutant is deleted in the RL1 gene and fails to produce the virulence factor ICP34.5. 1716 replication was analysed in both established human glioma cell lines and in primary cell cultures derived from human tumour biopsy material. In the majority of cultures, virus replication occurred and consequential cell death resulted. In the minority of tumour cell lines which are non-permissive for mutant replication, premature shut-off of host cell protein synthesis was induced in response to lack of expression of ICP34.5. Hence RL1-negative mutants have the distinct advantage of providing a double hit phenomenon whereby cell death could occur by either pathway. Moreover, 1716, by virtue of its ability to replicate selectively within a tumour cell, has the potential to deliver a 'suicide' gene product to the required site immediately. It is our opinion that HSV which fails to express ICP34.5 could provide an effective tumour therapy

The Birmingham Boron Neutron Capture Therapy (BNCT) project : developments towards selective internal particle therapy

This paper will review progress on two aspects of the Birmingham BNCT project. Firstly on evaluation of the effects of high and low LET radiations when delivered simultaneously, and secondly on attempts to optimise delivery of the boron carrier compound BPA through pharmacokinetic studies. Simultaneous or non-simultaneous irradiations of V79 cells with alpha-particle and X-ray irradiations were performed. Alpha doses of 2 and 2.5 Gy were chosen and the impact on survival when delivered separately or simultaneously with variable doses of X-rays was evaluated. The pharmacokinetics of the delivery of a new formulation of BPA (BPA-mannitol) are being investigated in brain tumour patients through a study with 2 × 2 design featuring intravenous and intracarotid artery infusion of BPA, with or without a mannitol bolus. On the combined effect of low and high LET radiations, a synergistic effect was observed when alpha and X-ray doses are delivered simultaneously. The effect is only present at the 2.5 Gy alpha dose and is a very substantial effect on both the shape of the survival curve and the level of cell killing. This indicates that the alpha component may have the effect of inhibiting the repair of damage from the low LET radiation dose delivered simultaneously. On the pharmacokinetics of BPA, data on the first three cohorts indicate that bioavailability of BPA in brain ECF is increased substantially through the addition of a mannitol bolus, as well as by the use of intracarotid artery route of infusion. In both cases, for some patients the levels after infusion approach those seen in blood, whereas the ECF levels for intravenous infusion without mannitol are typically less than 10% of the blood values

Acromegaly, Mr Punch and caricature.

The origin of Mr Punch from the Italian Pulcinella of the Commedia dell'arte is well known but his feature, large hooked nose, protruding chin, kyphosis and sternal protrusion all in an exaggerated form also suggest the caricature of an acromegalic. This paper looks at the physical characteristics of acromegaly, the origin of Mr Punch and the development of caricature linking them together in the acromegalic caricature that now has a life of its own

Cross-sectional survey of patients in receipt of long-term repeat prescriptions for antidepressant drugs in primary care

This cross-sectional survey describes the clinical characteristics of 92 patients from across 12 general medical practices, in receipt of a long-term repeat prescription of an antidepressant for the treatment of depression. Psychiatric diagnoses were determined using the Schedule for Clinical Assessment in Neuropsychiatry. Fifty-three participants (57.6%) failed to meet criteria for any psychiatric diagnosis (95% confidence interval (CI): 47.5–67.7%). Independent clinical assessments based upon diagnoses and other clinical data indicated that 26 (31.0%) participants (95% CI: 28.9–49.7%) had no clear clinical reason for continued receipt of an antidepressant. Reasons for the continued use of antidepressants in this population require further investigation

Cross-sectional survey of patients in receipt of long-term repeat prescriptions for antidepressant drugs in primary care

This cross-sectional survey describes the clinical characteristics of 92 patients from across 12 general medical practices, in receipt of a long-term repeat prescription of an antidepressant for the treatment of depression. Psychiatric diagnoses were determined using the Schedule for Clinical Assessment in Neuropsychiatry. Fifty-three participants (57.6%) failed to meet criteria for any psychiatric diagnosis (95% confidence interval (CI): 47.5–67.7%). Independent clinical assessments based upon diagnoses and other clinical data indicated that 26 (31.0%) participants (95% CI: 28.9–49.7%) had no clear clinical reason for continued receipt of an antidepressant. Reasons for the continued use of antidepressants in this population require further investigation

Where To from Here?

WATER IS GROWING in importance as a limiting factor in agriculture due to the unpredictable nature of rainfall and increasing competition for it from human and industrial uses. To sustain agricultural productivi- ty, water-use-efficient systems are required. Transpiration-efficient cultivars are an important component of such systems