Proof of Single-Replica Equivalence in Short-Range Spin Glasses.

We consider short-range Ising spin glasses in equilibrium at infinite system size, and prove that, for fixed bond realization and a given Gibbs state drawn from a suitable metastate, each translation and locally invariant function (for example, self-overlaps) of a single pure state in the decomposition of the Gibbs state takes the same value for all the pure states in that Gibbs state. We describe several significant applications to spin glasses.

Ground-state stability and the nature of the spin glass phase.

We propose an approach toward understanding the spin glass phase at zero and low temperature by studying the stability of a spin glass ground state against perturbations of a single coupling. After reviewing the concepts of flexibility, critical droplet, and related quantities for both finite- and infinite-volume ground states, we study some of their properties and review three models in which these quantities are partially or fully understood. We also review a recent result showing the connection between our approach and that of disorder chaos. We then view four proposed scenarios for the low-temperature spin glass phase-replica symmetry breaking, scaling-droplet, TNT, and chaotic pairs-through the lens of the predictions of each scenario for the lowest-energy large-lengthscale excitations above the ground state. Using a new concept called σ-criticality, which quantifies the sensitivity of ground states to single-bond coupling variations, we show that each of these four pictures can be identified with different critical droplet geometries and energies. We also investigate necessary and sufficient conditions for the existence of multiple incongruent ground states.

Long-time predictability in disordered spin systems following a deep quench.

We study the problem of predictability, or "nature vs nurture," in several disordered Ising spin systems evolving at zero temperature from a random initial state: How much does the final state depend on the information contained in the initial state, and how much depends on the detailed history of the system? Our numerical studies of the "dynamical order parameter" in Edwards-Anderson Ising spin glasses and random ferromagnets indicate that the influence of the initial state decays as dimension increases. Similarly, this same order parameter for the Sherrington-Kirkpatrick infinite-range spin glass indicates that this information decays as the number of spins increases. Based on these results, we conjecture that the influence of the initial state on the final state decays to zero in finite-dimensional random-bond spin systems as dimension goes to infinity, regardless of the presence of frustration. We also study the rate at which spins "freeze out" to a final state as a function of dimensionality and number of spins; here the results indicate that the number of "active" spins at long times increases with dimension (for short-range systems) or number of spins (for infinite-range systems). We provide theoretical arguments to support these conjectures, and also study analytically several mean-field models: the random energy model, the uniform Curie-Weiss ferromagnet, and the disordered Curie-Weiss ferromagnet. We find that for these models, the information contained in the initial state does not decay in the thermodynamic limit-in fact, it fully determines the final state. Unlike in short-range models, the presence of frustration in mean-field models dramatically alters the dynamical behavior with respect to the issue of predictability.

Universal protein distributions in a model of cell growth and division.

Protein distributions measured under a broad set of conditions in bacteria and yeast were shown to exhibit a common skewed shape, with variances depending quadratically on means. For bacteria these properties were reproduced by temporal measurements of protein content, showing accumulation and division across generations. Here we present a stochastic growth-and-division model with feedback which captures these observed properties. The limiting copy number distribution is calculated exactly, and a single parameter is found to determine the distribution shape and the variance-to-mean relation. Estimating this parameter from bacterial temporal data reproduces the measured distribution shape with high accuracy and leads to predictions for future experiments.

Thermodynamic Identities and Symmetry Breaking in Short-Range Spin Glasses.

We present a technique to generate relations connecting pure state weights, overlaps, and correlation functions in short-range spin glasses. These are obtained directly from the unperturbed Hamiltonian and hold for general coupling distributions. All are satisfied in phases with simple thermodynamic structure, such as the droplet-scaling and chaotic pairs pictures. If instead nontrivial mixed-state pictures hold, the relations suggest that replica symmetry is broken as described by a Derrida-Ruelle cascade, with pure state weights distributed as a Poisson-Dirichlet process.

Medical malpractice claims in relation to colorectal malignancy in the national health service.

AIM: Under the current increased financial constraints affecting the National Health Service (NHS), clinical negligence claims and associated compensations are constantly rising. Our aim was to identify the magnitude, trends and causes of malpractice claims in relation to a common pathology such as colorectal malignancy in the NHS. METHOD: Data requests were submitted to the NHS Litigation Authority (NHSLA) and to the Medical Defence Union (MDU) and Medical Protection Society (MPS). Data were reviewed, categorized clinically and analysed in terms of causes and costs behind claims. RESULTS: Data from the MPS and MDU were unavailable. In all, 169 claims were identified from the NHSLA database between 2003 and 2012; 123 (73%) cases had been closed, 80 (65%) of which were successful. An increasing overall claim frequency and success rate were found over the last few years. Total litigation expenses were £8.6 million, with 39% paid out as legal expenses. The commonest cause of complaint in successful claims was in relation to diagnostic delays or failures (58%, £5.1 million), with a delay or failure by the clinician to take action in response to an abnormal investigation result being a major factor. The occurrence of peri-operative complications (20%, £1.6 million) was the second commonest cause. CONCLUSION: Average frequency and success rates of malpractice claims in secondary care in the NHS are rising, leading to significant overall payouts. The failure or delay in diagnosing colorectal malignancy or its postoperative complications is a common cause behind malpractice claims. Improvement in these areas could enhance patient care and reduce future claims.

Nature versus nurture: predictability in low-temperature Ising dynamics.

Consider a dynamical many-body system with a random initial state subsequently evolving through stochastic dynamics. What is the relative importance of the initial state ("nature") versus the realization of the stochastic dynamics ("nurture") in predicting the final state? We examined this question for the two-dimensional Ising ferromagnet following an initial deep quench from T=∞ to T=0. We performed Monte Carlo studies on the overlap between "identical twins" raised in independent dynamical environments, up to size L=500. Our results suggest an overlap decaying with time as t(-θ)(h) with θ(h)=0.22 ± 0.02; the same exponent holds for a quench to low but nonzero temperature. This "heritability exponent" may equal the persistence exponent for the two-dimensional Ising ferromagnet, but the two differ more generally.

The majority of colorectal resections require an open approach, even in units with a special interest in laparoscopic surgery.

AIM: Proponents suggest that laparoscopic colorectal resection might be achievable in up to 90% of cases, while keeping conversion rates below 10%. This unselected prospective case series reports on the proportion of patients having a completed laparoscopic colorectal resection in two units where laparoscopic colorectal practice is well established and readily available. METHOD: All patients undergoing elective and emergency colorectal resection during a 6-month period were identified. The underlying pathology and the surgical approach (laparoscopic or open) were recorded. The contraindications to laparoscopic resection were also documented. The need and rationale for conversion to an open approach were recorded. RESULTS: In total, 205 consecutive patients (160 elective and 45 emergency procedures) underwent colorectal resection for malignancy [117 (57%) patients] and benign pathology [88 (43%) patients]. Laparoscopic resection was attempted in 127/205 (62%) patients and 31/127 (24%) of these were converted to open surgery. The main reasons for not attempting laparoscopic resection were locally advanced disease and emergency surgery. The commonest reasons for conversion were advanced disease and to allow completion of rectal dissection and/or cross-stapling of the rectum. CONCLUSION: Despite a special interest in laparoscopic colorectal surgery of the two colorectal units who provided the data for this study, fewer than half (96/205; 47%) of the patients in this consecutive unselected series who were undergoing major colorectal resection had the procedure completed laparoscopically.

Gene therapy progress and prospects: ultrasound for gene transfer.

Ultrasound exposure (USE) in the presence of microbubbles (MCB) (e.g. contrast agents used to enhance ultrasound imaging) increases plasmid transfection efficiency in vitro by several orders of magnitude. Formation of short-lived pores in the plasma membrane ('sonoporation'), up to 100 nm in effective diameter lasting a few seconds, is implicated as the dominant mechanism, associated with acoustic cavitation. Ultrasound enhanced gene transfer (UEGT) has also been successfully achieved in vivo, with reports of spatially restricted and therapeutically relevant levels of transgene expression. Loading MCB with nucleic acids and/or disease-targeting ligands may further improve the efficiency and specificity of UEGT such that clinical testing becomes a realistic prospect.

Ultrasound-mediated delivery of TIMP-3 plasmid DNA into saphenous vein leads to increased lumen size in a porcine interposition graft model.

Progressive saphenous vein graft (SVG) narrowing and occlusion remains a major limitation of coronary artery bypass grafting and is an important target for gene therapy. Ex vivo adenoviral gene transfer of tissue inhibitor of metalloproteinase 3 (TIMP-3) reduces adverse SVG remodelling postarterialization, but concerns remain over the use of viral vectors in patients. Ultrasound exposure (USE) in the presence of echocontrast microbubbles (ECM) substantially enhances nonviral gene delivery. We investigated the effects of ultrasound-enhanced gene delivery (UEGD) of TIMP-3 plasmid on vascular remodelling in porcine SVG. Maximal luciferase activity (3000-fold versus naked plasmid alone) and TIMP-3 transgene expression in porcine vascular smooth muscle cells in vitro was achieved using USE at 1 MHz, 1.8 mechanical index (MI), 6% duty cycle (DC) in the presence of 50% (v/v) BR14 ECM (Bracco). These conditions were therefore utilized for subsequent studies in vivo. Yorkshire White pigs received carotid interposition SVG that were untransfected or had undergone ex vivo UEGD of lacZ (control) or TIMP-3 plasmids. At 28 d postgrafting, lumen and total vessel area were significantly greater in the TIMP-3 group (10.1+/-1.2 and 25.5+/-2.2 mm2, respectively) compared to untransfected (6.34+/-0.5 and 20.8+/-1.9 mm2) or lacZ-transfected (6.1+/-0.7 and 19.7+/-1.2 mm2) controls (P<0.01). These data indicate that nonviral TIMP-3 plasmid delivery by USE achieves significant biological effects in a clinically relevant model of SV grafting, and is the first study to demonstrate the potential for therapeutic UEGD to prevent SVG failure.

Nonrealistic behavior of mean-field spin glasses.

We study chaotic size dependence of the low-temperature correlations in the Sherrington-Kirkpatrick (SK) spin glass. We prove that as temperature scales to zero with volume, for any typical coupling realization, the correlations cycle through every spin configuration in every fixed observation window. This cannot happen in short-ranged models as there it would mean that every spin configuration is an infinite-volume ground state. Its occurrence in the SK model means that the commonly used "modified clustering" notion of states sheds little light on the replica symmetry breaking (RSB) solution of SK, and, conversely, the RSB solution sheds little light on the thermodynamic structure of Edwards-Anderson models.

Drug eluting stents: maximising benefit and minimising cost.

A policy of selective implantation of drug eluting stents, in a minority of lesions most likely to benefit, seems to be a rational way to employ this new and currently costly technology.

The Brownian web.

Arratia, [Arratia, R. (1979) Ph.D. thesis (University of Wisconsin, Madison) and unpublished work] and later Toth and Werner [Toth, B. & Werner, W. (1998) Probab. Theory Relat. Fields 111, 375-452] constructed random processes that formally correspond to coalescing one-dimensional Brownian motions starting from every space-time point. We extend their work by constructing and characterizing what we call the Brownian Web as a random variable taking values in an appropriate (metric) space whose points are (compact) sets of paths. This leads to general convergence criteria and, in particular, to convergence in distribution of coalescing random walks in the scaling limit to the Brownian Web.

Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography.

OBJECTIVE: Current thinking is that amiodarone-induced thyrotoxicosis (AIT) might be either iodine-induced thyrotoxicosis in latent hyperthyroidism (Type 1) or destructive thyroiditis (Type 2), and also that colour-flow Doppler sonography (CFDS) of the thyroid and serum interleukin 6 (IL-6) are tools that can classify AIT and direct treatment. To assess the validity of this thinking, our objective was to determine whether CFDS and IL-6 identified AIT subgroups with distinct features. DESIGN: Retrospective case-note audit of all patients presenting with AIT to the Endocrine Department of a UK teaching hospital over a 3-year period. To assess proportions of Type 1 vs. Type 2 AIT and to compare and contrast their clinical features. PATIENTS: 37 patients were identified with AIT (mean age 65, range 20-86 years). In 30 patients in whom AIT persisted, 25 underwent CFDS. RESULTS: In 25 patients who underwent CFDS, 10 (40%) were classified as Type 1, 10 (40%) as Type 2 and 5 (20%) as indeterminate type. In the patients classified by CFDS in whom AIT persisted, 40% of Type 1 patients were male vs. 90% of Type 2 patients. Also, free T4 tended to be lower in patients presenting with Type 1 AIT (52.1 +/- 7.5 pmol/l) compared to Type 2 (74.8 +/- 8.1 pmol/l, P = 0.08), free T3 was lower (8.8 +/- 0.9 vs. 15.6 +/- 3.0 pmol/l, P = 0.03) and the cumulative amiodarone dose was lower (66 +/- 20 vs. 186 +/- 28 g, P = 0.002). We used less prednisolone to achieve euthyroidism in patients with Type 1 AIT whereas carbimazole doses were not different and the time to euthyroidism was the same in both groups (81 +/- 21 vs. 88 +/- 13 days). IL-6 was raised in two patients with Type 1 and in one patient with Type 2 AIT. CONCLUSIONS: CFDS could characterize two distinct subtypes in patients with AIT. Conversely, IL-6 seemed to be an unhelpful test in this context.

Aging in 1D discrete spin models and equivalent systems.

We derive exact expressions for a number of aging functions that are scaling limits of nonequilibrium correlations, R(t(w),t(w)+t) as t(w)-->infinity, t/t(w)-->theta, in the 1D homogenous q-state Potts model for all q with T = 0 dynamics following a quench from T = infinity. One such quantity is (0)(t(w));sigma-->(n)(t(w)+t)> when n/square root of ([t(w))-->z. Exact, closed-form expressions are also obtained when an interlude of T = infinity dynamics occurs. Our derivations express the scaling limit via coalescing Brownian paths and a "Brownian space-time spanning tree," which also yields other aging functions, such as the persistence probability of no spin flip at 0 between t(w) and t(w)+t.

Interfaces and the question of regional congruence in spin glasses.

We present a general theorem restricting properties of interfaces between thermodynamic states and apply it to the spin glass excitations observed numerically by Krzakala and Martin and separately by Palassini and Young in spatial dimensions d = 3,4. We show that such excitations, with interface dimension d(s) < d, cannot yield regionally congruent thermodynamic states. More generally, zero density interfaces of translation-covariant excitations cannot be pinned (by the disorder) in any d but rather must deflect to infinity in the thermodynamic limit. Additional consequences concerning regional congruence in spin glasses and other systems are discussed.

Ultrasound gene therapy: on the road from concept to reality.

The promise of gene therapy lies in the potential to ameliorate or cure conditions that are resistant to conventional therapeutic approaches. Progress in vascular and all other fields of gene therapy has been hampered by concerns over the safety and practicality of recombinant viral vectors and the inefficiency of current nonviral transfection techniques. This review summarizes the increasing evidence that exposure of eukaryotic cells to relatively modest intensity ultrasound, within the range emitted by diagnostic transducers, either alone or in combination with other nonviral techniques, can enhance transgene expression by up to several orders of magnitude over naked DNA alone. In combination with the flexibility and excellent clinical safety profile of therapeutic and diagnostic ultrasound, these data suggest that ultrasound-assisted gene delivery has great promise as a novel approach to improve the efficiency of many forms of nonviral gene delivery.

Realistic spin glasses below eight dimensions: A highly disordered view.

By connecting realistic spin glass models at low temperature to the highly disordered model at zero temperature, we argue that ordinary Edwards-Anderson spin glasses below eight dimensions have at most a single pair of physically relevant pure states at nonzero low temperature. Less likely scenarios that evade this conclusion are also discussed.

Microbubble-enhanced ultrasound for vascular gene delivery.

Progress in cardiovascular gene therapy has been hampered by concerns over the safety and practicality of viral vectors and the inefficiency of current nonviral transfection techniques. We have previously reported that ultrasound exposure (USE) enhances transgene expression in vascular cells by up to 10-fold after naked DNA transfection, and enhances lipofection by up to three-fold. We report here that performing USE in the presence of microbubble echocontrast agents enhances acoustic cavitation and is associated with approximately 300-fold increments in transgene expression after naked DNA transfections. This approach also enhances by four-fold the efficiency of polyplex transfection, yielding transgene expression levels approximately 3000-fold higher than after naked DNA alone. These data indicate an important role for acoustic cavitation in the effects of USE. Ultrasound can be focused upon almost any organ and hence this approach holds promise as a means to deliver targeted gene therapy in cardiovascular conditions such as such angioplasty restenosis and in many other clinical situations.