Creating historical controls using data from a previous line of treatment – Two non-standard approaches

Where medical interventions are licensed based on only uncontrolled study data (for example a single-arm trial), a common approach for estimating the incremental benefit is to compare the treatment to a 'historical control'; data collected from patients who did not receive the intervention. We illustrate with motivating examples two methods for the creation of historical controls where disease progression and overall survival are typically the key clinically meaningful endpoints. The first method utilises information routinely collected in a clinical trial programme: patients' time to disease progression on their previous line of treatment against which outcomes can be compared. The second uses published clinical outcomes for the prior line of treatment which can be extrapolated to estimate outcomes at the next line. As examples we use two pharmaceuticals licensed on the basis of uncontrolled clinical studies - idelalisib for double-refractory follicular lymphoma and ofatumumab for double-refractory chronic lymphocytic leukemia. Although subject to limitations that should be considered on a case-by-case basis, the methods may be appropriate when trying to quantify the clinical benefit of treatment based on limited and uncontrolled trial data. As a result, the methods can be used to inform health technology adoption decisions

Acoustic black holes for relativistic fluids

We derive a new acoustic black hole metric from the Abelian Higgs model. In the non-relativistic limit, while the Abelian Higgs model becomes the Ginzburg-Landau model, the metric reduces to an ordinary Unruh type. We investigate the possibility of using (type I and II) superconductors as the acoustic black holes. We propose to realize experimental acoustic black holes by using spiral vortices solutions from the Navier-stokes equation in the non-relativistic classical fluids.Comment: 16 pages. typos corrected, contents expande

Three-dimensional cephalometric evaluation of maxillary growth following in utero repair of cleft lip and alveolar-like defects in the mid-gestational sheep model

Objective: To evaluate maxillary growth following in utero repair of surgically created cleft lip and alveolar (CLA)-like defects by means of three-dimensional (3D) computer tomographic (CT) cephalometric analysis in the mid-gestational sheep model. Methods: In 12 sheep fetuses a unilateral CLA-like defect was created in utero (untreated control group: 4 fetuses). Four different bone grafts were used for the alveolar defect closure. After euthanasia, CT scans of the skulls of the fetuses, 3D re-constructions, and a 3D-CT cephalometric analysis were performed. Results: The comparisons between the operated and nonoperated skull sides as well as of the maxillary asymmetry among the experimental groups revealed no statistically significant differences of the 12 variables used. Conclusions: None of the surgical approaches used for the in utero correction of CLA-like defects seem to affect significantly postsurgical maxillary growth; however, when bone graft healing takes place, a tendency for almost normal maxillary growth can be observed. Copyright (c) 2006 S. Karger AG, Basel

One-sided versus two-sided stochastic descriptions

It is well-known that discrete-time finite-state Markov Chains, which are described by one-sided conditional probabilities which describe a dependence on the past as only dependent on the present, can also be described as one-dimensional Markov Fields, that is, nearest-neighbour Gibbs measures for finite-spin models, which are described by two-sided conditional probabilities. In such Markov Fields the time interpretation of past and future is being replaced by the space interpretation of an interior volume, surrounded by an exterior to the left and to the right. If we relax the Markov requirement to weak dependence, that is, continuous dependence, either on the past (generalising the Markov-Chain description) or on the external configuration (generalising the Markov-Field description), it turns out this equivalence breaks down, and neither class contains the other. In one direction this result has been known for a few years, in the opposite direction a counterexample was found recently. Our counterexample is based on the phenomenon of entropic repulsion in long-range Ising (or "Dyson") models.Comment: 13 pages, Contribution for "Statistical Mechanics of Classical and Disordered Systems

On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm

N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al

Neocortical hyperexcitability in a genetic model of absence seizures and its reduction by levetiracetam

PURPOSE: To study the effect of the antiepileptic drug levetiracetam (LEV) on the patterns of intrinsic optical signals (IOSs) generated by slices of the somatosensory cortex obtained from 3- and 6-month-old WAG/Rij and age-matched, nonepileptic control (NEC) rats. METHODS: WAG/Rij and NEC animals were anesthetized with enfluorane and decapitated. Brains were quickly removed, and neocortical slices were cut coronally with a vibratome, transferred to a submerged tissue chamber, and superfused with oxygenated artificial cerebrospinal fluid (aCSF). Slices were illuminated with a dark-field condensor and examined with a x2.5 objective; images were processed with a real time digital video image-enhancement system. Images were acquired before (background) and during electrical stimulation with a temporal resolution of 10 images/s and were displayed in pseudocolors. Extracellular stimuli (200 micros; <4 V) were delivered through bipolar stainless steel electrodes placed in the white matter. RESULTS: IOSs recorded in NEC slices bathed in control aCSF became less intense and of reduced size with age (p < 0.05); this trend was not seen in WAG/Rij slices. Age-dependent decreases in IOS intensity and area size were also seen in NEC slices superfused with aCSF containing the convulsant 4-aminopyridine (4-AP, 5 microM); in contrast, significant increases in both parameters occurred with age in 4-AP-treated WAG/Rij slices (p < 0.05). Under any of these conditions, the IOS intensity and area size slices were larger in WAG/Rij than in NEC slices. LEV (50-500 microM) application to WAG/Rij slices caused dose-dependent IOS reductions that were evident both in control and in 4-AP-containing aCSF and were more pronounced in 6-month-old tissue. CONCLUSIONS: These data demonstrate age-dependent IOS modifications in NEC and WAG/Rij rat slices and identify a clear pattern of hyperexcitability that occurs in 6-month-old WAG/Rij neocortical tissue, an age when absence seizures occur in all animals. The ability of LEV to reduce these patterns of network hyperexcitability supports the potential use of this new antiepileptic drug in primary generalized epileptic disorders

Influence of Reoperations on Long-Term Quality of Life After Restrictive Procedures: A Prospective Study

Quality of life improves after bariatric surgery. However, long-term results and the influence of reoperations are not well known. A prospective quality of life assessment before, 1 and 7 years after laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG) was performed in order to determine the influence of reoperations during follow-up. One hundred patients were included in the study. Fifty patients underwent VBG and 50 LAGB. Patients completed the quality of life questionnaires prior to surgery and two times during follow-up. Health-related quality of life (HRQoL) questionnaires included the Nottingham Health Profile I and II and the Sickness Impact Profile 68. Follow-up was 84% with a mean duration of 84 months (7 years). During follow-up, 65% of VBG patients underwent conversion to Roux-en-Y gastric bypass while 44% of LAGB patients underwent a reoperation or conversion. One year after the procedure, nearly all quality-of-life parameters significantly improved. After 7 years, the Nottingham Health Profile (NHP)-I domain “physical ability”, the NHP-II and the SIP-68 domains “mobility control”, “social behavior”, and “mobility range” were still significantly improved in both groups. The domains “emotional reaction”, “social isolation” (NHP-I), and “emotional stability” (SIP-68) remained significantly improved in the VBG group while this was true for the domain “energy level” (NHP-I) in the LAGB group. Both the type of procedure and reoperations during follow-up were not of significant influence on the HRQoL results. Weight loss and decrease in comorbidities were the only significant factors influencing quality of life. Restrictive bariatric surgery improves quality of life. Although results are most impressive 1 year after surgery, the improvement remains significant after long-term follow-up. Postoperative quality of life is mainly dependent on weight loss and decrease in comorbidities and not on the type of procedure or surgical complications

Bottom-up assembly of metallic germanium

Extending chip performance beyond current limits of miniaturisation requires new materials and functionalities that integrate well with the silicon platform. Germanium fits these requirements and has been proposed as a high-mobility channel material, a light emitting medium in silicon-integrated lasers, and a plasmonic conductor for bio-sensing. Common to these diverse applications is the need for homogeneous, high electron densities in three-dimensions (3D). Here we use a bottom-up approach to demonstrate the 3D assembly of atomically sharp doping profiles in germanium by a repeated stacking of two-dimensional (2D) high-density phosphorus layers. This produces high-density (1019 to 1020 cm-3) low-resistivity (10-4Ω ∙ cm) metallic germanium of precisely defined thickness, beyond the capabilities of diffusion-based doping technologies. We demonstrate that free electrons from distinct 2D dopant layers coalesce into a homogeneous 3D conductor using anisotropic quantum interference measurements, atom probe tomography, and density functional theory

First metatarsophalangeal hemiarthroplasty for hallux rigidus

There is a paucity of objective information in the literature about first metatarsophalangeal (MTP) hemiarthroplasty. The authors postulate that it is a reasonable treatment option for severe hallux rigidus in selected patients. Twenty-two elective first MTP hemiarthroplasties were performed on 20 patients that met the inclusion criteria. Pre- and postoperative evaluations were done using the American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score, visual analogue scale (VAS) pain score, range of motion (ROM) measurements, and radiographs. Average ROM and dorsiflexion improved by 15° and 8°, respectively. VAS pain scores improved from 5 to 2.5 after six weeks. Painless ambulation occurred after six weeks, with maximum improvement by six months. After 24 months, two patients had pain at the surgical site interfering with function, leading to an unsatisfactory result that required conversion to arthrodesis. First MTP hemiarthroplasty for severe hallux rigidus can be considered an alternative to fusion in properly selected patients who wish to maintain a functional range of motion