CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Evolutionary Epidemiology Consequences of Trait-Dependent Control of Heterogeneous Parasites.

AbstractDisease control can induce both demographic and evolutionary responses in host-parasite systems. Foreseeing the outcome of control therefore requires knowledge of the eco-evolutionary feedback between control and system. Previous work has assumed that control strategies have a homogeneous effect on the parasite population. However, this is not true when control targets those traits that confer to the parasite heterogeneous levels of resistance, which can additionally be related to other key parasite traits through evolutionary trade-offs. In this work, we develop a minimal model coupling epidemiological and evolutionary dynamics to explore possible trait-dependent effects of control strategies. In particular, we consider a parasite expressing continuous levels of a trait-determining resource exploitation and a control treatment that can be either positively or negatively correlated with that trait. We demonstrate the potential of trait-dependent control by considering that the decision maker may want to minimize both the damage caused by the disease and the use of treatment, due to possible environmental or economic costs. We identify efficient strategies showing that the optimal type of treatment depends on the amount applied. Our results pave the way for the study of control strategies based on evolutionary constraints, such as collateral sensitivity and resistance costs, which are receiving increasing attention for both public health and agricultural purposes.

Effects of orientational order on modulated cylindrical interfaces.

Cylindrical interfaces occur in sheared or deformed emulsions and as biological or technological lipid monolayer or bilayer tubules. Like the corresponding spherical droplets and vesicles, these cylinderlike surfaces may host orientational order with n-fold rotational symmetry, for example in the positions of lipid molecules or of spherical nanoparticles. We examine how that order interacts with and induces shape modulations of cylindrical interfaces. While on spherical droplets 2n topological defects necessarily exist and can induce icosahedral droplet shapes, the cylindrical topology is compatible with a defect-free patterning. Nevertheless, once a modulation is introduced by a mechanism such as spontaneous curvature, nontrivial patterns of order, including ones with excess defects, emerge and have nonlinear effects on the shape of the tube. By examining the equilibrium energetics of the system analytically and with a lattice-based Markov chain Monte Carlo simulation, we predict low-temperature morphologies of modulated cylindrical interfaces hosting orientational order. A shape modulation induces a banded pattern of alternatingly isotropic and ordered interfacial material. Furthermore, cylindrical systems can be divided into type I, without defects, and type II, which go through a spectrum of defect states with up to 4n excess defects. The character of the curvature-induced shape transition from unmodulated to modulated cylinders is continuous or discontinuous accordingly.

Redundancy-selection trade-off in phenotype-structured populations.

Realistic fitness landscapes generally display a redundancy-fitness trade-off: highly fit trait configurations are inevitably rare, while less fit trait configurations are expected to be more redundant. The resulting sub-optimal patterns in the fitness distribution are typically described by means of effective formulations, where redundancy provided by the presence of neutral contributions is modelled implicitly, e.g. with a bias of the mutation process. However, the extent to which effective formulations are compatible with explicitly redundant landscapes is yet to be understood, as well as the consequences of a potential miss-match. Here we investigate the effects of such trade-off on the evolution of phenotype-structured populations, characterised by continuous quantitative traits. We consider a typical replication-mutation dynamics, and we model redundancy by means of two dimensional landscapes displaying both selective and neutral traits. We show that asymmetries of the landscapes will generate neutral contributions to the marginalised fitness-level description, that cannot be described by effective formulations, nor disentangled by the full trait distribution. Rather, they appear as effective sources, whose magnitude depends on the geometry of the landscape. Our results highlight new important aspects on the nature of sub-optimality. We discuss practical implications for rapidly mutant populations such as pathogens and cancer cells, where the qualitative knowledge of their trait and fitness distributions can drive disease management and intervention policies.

Ghost-patterning and non-patterning in a draining film model.

Patterns can form when the uniform state of any system is unstable so that some non-uniform motif grows in amplitude. Here, we identify an alternative way to form non-trivial structures, which we call "ghost-patterns". Ghost-patterns emerge from noisy initial conditions when all non-uniform modes decay in amplitude except for one non-trivial motif which fails to decay. Hence, in seeking structured states, it is not necessary to find positive growth rates. We demonstrate ghost-patterns in an idealized non-equilibrium model intended to emulate draining thin-film suspensions.

Pay-off scarcity causes evolution of risk-aversion and extreme altruism.

All organisms descend from populations with limited resources, so it is clear why evolution should select strategies that win resources at the expense of competitors. Less obvious is how altruistic behaviours evolve, whereby an individual helps others despite expense to itself. Modelling simple agents using evolutionary game theory, it is shown that steady states of extreme altruism can evolve when pay-offs are very rare compared with death. In these states, agents give away most of their wealth. A new theorem for general evolutionary models shows that, when pay-offs are rare, evolution no longer selects strategies to maximize income (average pay-off), but to minimize the risk of missing-out entirely on a rare resource. Principles revealed by the model are widely applicable, where the game represents rare life-changing events: disasters or gluts.

Generating single metalloprotein crystals in well-defined redox states: electrochemical control combined with infrared imaging of a NiFe hydrogenase crystal.

We describe an approach to generating and verifying well-defined redox states in metalloprotein single crystals by combining electrochemical control with synchrotron infrared microspectroscopic imaging. For NiFe hydrogenase 1 from Escherichia coli we demonstrate fully reversible and uniform electrochemical reduction from the oxidised inactive to the fully reduced state, and temporally resolve steps during this reduction.

Is confirmation of ureteric stent placement in laparoscopic pyeloplasty necessary?

PURPOSE: Placement of an antegrade double-J (JJ) ureteric stent is an important component of pyeloplasty. Correct siting of distal end of the stent in the bladder is essential for ease of removal. To date, no studies have compared methods for confirming stent position. This study aims to address that void in the literature. METHODS: Eligible patients underwent laparoscopic pyeloplasty with antegrade stent placement at our institution from 2007 to 2015 inclusive. Methods to verify distal stent position of rigid cystoscopy, artificial bladder filling or no confirmation were compared. Effectiveness was determined by the proportion of malpositioned stents detected intra-operatively compared to the total found malpositioned, both intra-operatively and during follow-up. RESULTS: A total of 75 patients underwent laparoscopic pyeloplasty. Forty-six (61.3%) patients had distal stent position assessed intra-operatively, comprising 27 by cystoscopy and 19 by artificial bladder filling, while for 29 (38.7%) patients no verification method was used. Cystoscopy, artificial bladder filling and no confirmation detected intra-operatively 2, 1 and 0 malpositioned stents, from malpositioned stent totals of 2, 2 and 1, respectively. CONCLUSION: Malposition of JJ ureteric stent is uncommon, and omitting intra-operative position verification appears reasonable in select cases. Artificial bladder filling can help detect malpositioned JJ stents without repositioning the patient for cystoscopy. However, our results suggest both may be unreliable. If stent malposition is suspected, certainty is desired or extended operative duration is less critical, then the surgeon should proceed with cystoscopy.

Modern Radiology in the Management of Head and Neck Cancer.

The accurate staging of head and neck cancer is vital to direct appropriate management strategies and to deliver the best radiation therapy and surgery. Initial challenges in head and neck cancer imaging include determination of T- and N-stage, stage migration with detection of metastatic disease and identification of primary disease in the patient presenting with nodal metastases. In follow-up, imaging has an important role in assessing patients who may require salvage surgery after radiotherapy and assessing clinical change that may represent either residual/recurrent disease or radiation effects. This overview gathers recent evidence on the optimal use of currently readily available imaging modalities (ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography-computed tomography) in the context of head and neck squamous cell cancers.

Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases.

The vitamin D receptor (VDR) is a ligand-activated transcription factor that regulates gene expression in many cell types, including immune cells. It requires binding of 1,25 dihydroxy vitamin D3 (1,25D3) for activation. Many autoimmune diseases show latitude-dependent prevalence and/or association with vitamin D deficiency, and vitamin D supplementation is commonly used in their clinical management. 1,25D3 is regulated by genes associated with the risk of autoimmune diseases and predominantly expressed in myeloid cells. We determined the VDR cistrome in monocytes and monocyte-derived inflammatory (DC1) and tolerogenic dendritic cells (DC2). VDR motifs were highly overrepresented in ChIP-Seq peaks in stimulated monocyte (40%), DC1 (21%) and DC2 (47%), P

The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease.

Activation of peroxisome proliferator-activated receptors (PPARs), namely PPARγ and PPARδ, has been shown to provide neuroprotection in a number of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease (PD). The observed neuroprotective effects in experimental models of PD have been linked to anti-oxidant and anti-inflammatory actions. This study aimed to analyze the full influence of these receptors in neuroprotection by generating a nerve cell-specific conditional knock-out of these receptors and subjecting these genetically modified mice to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to model dopaminergic degeneration. Mice null for both receptors show the lowest levels of tyrosine hydroxylase (TH)-positive cell bodies following MPTP administration. Presence of one or both these receptors show a trend toward protection against this degeneration, as higher dopaminergic cell immunoreactivity and striatal monoamine levels are evident. These data supplement recent studies that have elected to use agonists of the receptors to regulate immune responses. The results place further importance on the activation of PPARs and the neuroprotective roles these have in inflammatory processes linked to neurodegenerative processes.

Classical XY model with conserved angular momentum is an archetypal non-Newtonian fluid.

We find that the classical one-dimensional XY model, with angular-momentum-conserving Langevin dynamics, mimics the non-Newtonian flow regimes characteristic of soft matter when subjected to counterrotating boundaries. An elaborate steady-state phase diagram has continuous and first-order transitions between states of uniform flow, shear-banding, solid-fluid coexistence and slip planes. Results of numerical studies and a concise mean-field constitutive relation offer a paradigm for diverse nonequilibrium complex fluids.

The treatment of a rupture of the Achilles tendon using a dedicated management programme.

The Swansea Morriston Achilles Rupture Treatment (SMART) programme was introduced in 2008. This paper summarises the outcome of this programme. Patients with a rupture of the Achilles tendon treated in our unit follow a comprehensive management protocol that includes a dedicated Achilles clinic, ultrasound examination, the use of functional orthoses, early weight-bearing, an accelerated exercise regime and guidelines for return to work and sport. The choice of conservative or surgical treatment was based on ultrasound findings. The rate of re-rupture, the outcome using the Achilles Tendon Total Rupture Score (ATRS) and the Achilles Tendon Repair Score, (AS), and the complications were recorded. An elementary cost analysis was also performed. Between 2008 and 2014 a total of 273 patients presented with an acute rupture 211 of whom were managed conservatively and 62 had surgical repair. There were three re-ruptures (1.1%). There were 215 men and 58 women with a mean age of 46.5 years (20 to 86). Functional outcome was satisfactory. Mean ATRS and AS at four months was 53.0 (sd 14), 64.9 (sd 15) (n = 135), six months 67.8 (sd 16), 73.8 (sd 15) (n = 103) and nine months (72.4; sd 14) 72.3 (sd 13) (n = 43). The programme realised estimated cost savings exceeding £91,000 per annum. The SMART programme resulted in a low rate of re-rupture, a satisfactory outcome, a reduced rate of surgical intervention and a reduction in healthcare costs.

Measuring local volume fraction, long-wavelength correlations, and fractionation in a phase-separating polydisperse fluid.

We dynamically simulate fractionation (partitioning of particle species) during spinodal gas-liquid separation of a size-polydisperse colloid, using polydispersity up to ~40% and a skewed parent size distribution. We introduce a novel coarse-grained Voronoi method to minimise size bias in measuring local volume fraction, along with a variety of spatial correlation functions which detect fractionation without requiring a clear distinction between the phases. These can be applied whether or not a system is phase separated, to determine structural correlations in particle size, and generalise easily to other kinds of polydispersity (charge, shape, etc.). We measure fractionation in both mean size and polydispersity between the phases, its direction differing between model interaction potentials which are identical in the monodisperse case. These qualitative features are predicted by a perturbative theory requiring only a monodisperse reference as input. The results show that intricate fractionation takes place almost from the start of phase separation, so can play a role even in nonequilibrium arrested states. The methods for characterisation of inhomogeneous polydisperse systems could in principle be applied to experiment as well as modelling.

Numerical comparison of a constrained path ensemble and a driven quasisteady state.

We investigate the correspondence between a nonequilibrium ensemble defined via the distribution of phase-space paths of a Hamiltonian system and a system driven into a steady state by nonequilibrium boundary conditions. To discover whether the nonequilibrium path ensemble adequately describes the physics of a driven system, we measure transition rates in a simple one-dimensional model of rotors with Newtonian dynamics and purely conservative interactions. We compare those rates with known properties of the nonequilibrium path ensemble. In doing so, we establish effective protocols for the analysis of transition rates in nonequilibrium quasisteady states. Transition rates between potential wells and also between phase-space elements are studied and found to exhibit distinct properties, the more coarse-grained potential wells being effectively further from equilibrium. In all cases the results from the boundary-driven system are close to the path-ensemble predictions, but the question of equivalence of the two remains open.

Intense pulsed light treatment of chronic mid-body Achilles tendinopathy: A double blind randomised placebo-controlled trial.

We conducted a randomised controlled trial to determine whether active intense pulsed light (IPL) is an effective treatment for patients with chronic mid-body Achilles tendinopathy. A total of 47 patients were randomly assigned to three weekly therapeutic or placebo IPL treatments. The primary outcome measure was the Victorian Institute of Sport Assessment - Achilles (VISA-A) score. Secondary outcomes were a visual analogue scale for pain (VAS) and the Lower Extremity Functional Scale (LEFS). Outcomes were recorded at baseline, six weeks and 12 weeks following treatment. Ultrasound assessment of the thickness of the tendon and neovascularisation were also recorded before and after treatment. There was no significant difference between the groups for any of the outcome scores or ultrasound measurements by 12 weeks, showing no measurable benefit from treatment with IPL in patients with Achilles tendinopathy.

A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.

Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson's disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 µM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP⁺) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 µM). GW0742 alone did not affect MPP⁺ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 µg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036±195) when compared to vehicle-infused mice (3953±460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.

Spinodal fractionation in a polydisperse square-well fluid.

Using kinetic Monte Carlo simulation, we model gas-liquid spinodal decomposition in a size-polydisperse square well fluid, representing a "near-monodisperse" colloidal dispersion. We find that fractionation (demixing) of particle sizes between the phases begins asserting itself shortly after the onset of phase ordering. Strikingly, the direction of size fractionation can be reversed by a seemingly trivial choice between two interparticle potentials which, in the monodisperse case, are identical--we rationalize this in terms of a perturbative, equilibrium theory of polydispersity. Furthermore, our quantitative results show that kinetic Monte Carlo simulation can provide detailed insight into the role of fractionation in real colloidal systems.

Timing and magnitude of C partitioning through a young loblolly pine (Pinus taeda L.) stand using 13C labeling and shade treatments.

The dynamics of rapid changes in carbon (C) partitioning within forest ecosystems are not well understood, which limits improvement of mechanistic models of C cycling. Our objective was to inform model processes by describing relationships between C partitioning and accessible environmental or physiological measurements, with a special emphasis on short-term C flux through a forest ecosystem. We exposed eight 7-year-old loblolly pine (Pinus taeda L.) trees to air enriched with (13)CO(2) and then implemented adjacent light shade (LS) and heavy shade (HS) treatments in order to manipulate C uptake and flux. The impacts of shading on photosynthesis, plant water potential, sap flow, basal area growth, root growth and soil CO(2) efflux rate (CER) were assessed for each tree over a 3-week period. The progression of the (13)C label was concurrently tracked from the atmosphere through foliage, phloem, roots and surface soil CO(2) efflux. The HS treatment significantly reduced C uptake, sap flow, stem growth and fine root standing crop, and resulted in greater residual soil water content to 1 m depth. Soil CER was strongly correlated with sap flow on the previous day, but not the current day, with no apparent treatment effect on the relationship. Although there were apparent reductions in new C flux belowground, the HS treatment did not noticeably reduce the magnitude of belowground autotrophic and heterotrophic respiration based on surface soil CER, which was overwhelmingly driven by soil temperature and moisture. The (13)C label was immediately detected in foliage on label day (half-life = 0.5 day), progressed through phloem by Day 2 (half-life = 4.7 days), roots by Days 2-4, and subsequently was evident as respiratory release from soil which peaked between Days 3 and 6. The δ(13)C of soil CO(2) efflux was strongly correlated with phloem δ(13)C on the previous day, or 2 days earlier. While the (13)C label was readily tracked through the ecosystem, the fate of root C through respiratory, mycorrhizal or exudative release pathways was not assessed. These data detail the timing and relative magnitude of C flux through various components of a young pine stand in relation to environmental conditions.

Nuclear receptors and AMPK: resetting metabolism.

Obesity, and in particular central adiposity, is a key feature of metabolic syndrome, which includes trends toward increased triglycerides, insulin resistance, high blood pressure, hypercholesterolemia, and heart disease. It has a prevalence of 25% or more and is a dominant component of the health care budgets in Western societies. In addition to genetic causes, high-fat diets and disrupted sleep patterns have major influences on the development of metabolic syndrome. Recent studies have demonstrated active roles for the nuclear receptor superfamily and the energy-sensing kinase adenosine monophosphate (AMP)-activated protein kinase (AMPK) in regulating metabolism and circadian rhythm. In this chapter, we review these findings and attempt to develop a better understanding of the interplay between metabolism and circadian rhythm and their coordinated regulation by nuclear receptors and AMPK. This supraregulatory network may be considered a target for novel therapeutic applications against metabolic syndrome.