Asynchronous parallel branch and bound and anomalies

The parallel execution of branch and bound algorithms can result in seemingly unreasonable speedups or slowdowns. Almost never the speedup is equal to the increase in computing power. For synchronous parallel branch and bound, these effects have been studiedd extensively. For asynchronous parallelizations, only little is known. In this paper, we derive sufficient conditions to guarantee that an asynchronous parallel branch and bound algorithm (with elimination by lower bound tests and dominance) will be at least as fast as its sequential counterpart. The technique used for obtaining the results seems to be more generally applicable. The essential observations are that, under certain conditions, the parallel algorithm will always work on at least one node, that is branched from by the sequential algorithm, and that the parallel algorithm, after elimination of all such nodes, is able to conclude that the optimal solution has been found. Finally, some of the theoretical results are brought into connection with a few practical experiments

Towards an abstract parallel branch and bound machine

Many (parallel) branch and bound algorithms look very different from each other at first glance. They exploit, however, the same underlying computational model. This phenomenon can be used to define branch and bound algorithms in terms of a set of basic rules that are applied in a specific (predefined) order. In the sequential case, the specification of Mitten's rules turns out to be sufficient for the development of branch and bound algorithms. In the parallel case, the situation is a bit more complicated. We have to consider extra parameters such as work distribution and knowledge sharing. Here, the implementation of parallel branch and bound algorithms can be seen as a tuning of the parameters combined with the specification of Mitten's rules. These observations lead to generic systems, where the user provides the specifications of the problem to be solved, and the system generates a branch and bound algorithm running on a specific architecture. We will discuss some proposals that appeared in the literature. Next, we raise the question whether the proposed models are flexible enough. We analyze the design decisions to be taken when implementing a parallel branch and bound algorithm. It results in a classification model, which is validated by checking whether it captures existing branch and bound implementations. Finally, we return to the issue of flexibility of existing systems, and propose to add an abstract machine model to the generic framework. The model defines a virtual parallel branch and bound machine, within which the design decisions can be expressed in terms of the abstract machine. We will outline some ideas on which the machine may be based, and present directions of future work

Kommerell’s diverticulum and aneurysmal right-sided aortic arch: A case report and review of the literature

AbstractRight-sided aortic arch is a rare variant of the thoracic vascular anatomy that may be accompanied by an aberrant origin of the left subclavian artery. We report a true aneurysm of the distal arch and descending thoracic aorta in a patient with right-sided arch and review previous descriptions of aneurysms of anomalous right-sided aortas. In our patient, the left subclavian artery originated at the junction between the distal arch and the descending thoracic aorta located in the right chest and was aneurysmal (Kommerell’s diverticulum); the thoracic aorta was also aneurysmal. Extra-anatomic left subclavian-to-carotid transposition was performed before the intrathoracic procedure. Subsequently, a right thoracotomy provided adequate exposure for repairing the aortic aneurysm and oversewing the aneurysmal origin of the subclavian artery. Because the distal aortic arch was involved, deep hypothermia and circulatory arrest were used. Only five previous instances of true aneurysms of a right-sided aortic arch have been reported; four of these patients underwent operative repair (via bilateral thoracotomy, median sternotomy, or right thoracotomy). We believe that a right thoracotomy provides good exposure and avoids the morbidity associated with bilateral thoracotomy. The reconstruction of the subclavian artery has not previously been reported in this setting. Performing subclavian reconstruction as an extrathoracic procedure before the intrathoracic repair would be expected to reduce the subsequent risk of distal ischemia or subclavian steal without increasing the overall morbidity associated with the procedure. (J Vasc Surg 2000;32:1208-14.

An object oriented approach to generic branch and bound

Branch and bound algorithms can be characterized by a small set of basic rules that are applied in a divide-and-conquer-like framework. The framework is about the same in all applications, whereas the specification of the rules is problem dependent. Building a framework is a rather simple task in sequential implementations, but must not be underestimated in the parallel case, especially if an efficient branch and bound algorithm is required. In generic branch and bound models, the basic rules can be clearly identified within the framework, and, hence, it can be developed independently from the application. Furthermore, it gives the user the opportunity to concentrate on the actual problem to be solved, without being distracted by user-irrelevant issues like the properties of the underlying architecture. In this paper, we will discuss an object oriented approach to generic branch and bound. We will show how object orientation can help us to build a flexible branch and bound framework, that is able to perform like any branch and bound algorithm that fits into some powerful taxonomies known from the literature. We will define an interface for the specification of the problem dependent parts, and we will give a first indication of how the user can tune the framework if a non-default behavior is desired

Comparison of pharmacokinetics, safety and tolerability of secukinumab administered subcutaneously using different delivery systems in healthy volunteers and in psoriasis patients

Publisher Copyright: © 2019 Novartis. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological SocietyAims: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. Methods: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1-mL prefilled syringe or 1 × 2-mL prefilled syringe. Results: Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1-year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusion: Collective evidence from both studies demonstrated that 2-mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.Peer reviewe

Secukinumab immunogenicity over 52 weeks in patients with psoriatic arthritis and ankylosing spondylitis

Objective. Secukinumab, a fully human antiinterleukin 17A monoclonal antibody, is efficacious for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). This study examined the immunogenicity of secukinumab in patients with PsA and AS exposed to secukinumab for up to 52 weeks. Methods. Antibody bridging assays were used to assess the immunogenicity of secukinumab in patients with PsA [FUTURE 1–3 studies, and AS (MEASURE 1–4 studies)]. Evaluations were at baseline and at weeks 16 (AS only), 24, and 52. Treatment-emergent antidrug antibodies (TE-ADA) were defined as a positive ADA signal in ≥ 1 posttreatment sample in patients negative at baseline. Positive samples were analyzed for drug-neutralizing potential, and effect of TE-ADA on secukinumab pharmacokinetics, immunogenicity-related adverse events (AE), and efficacy through Week 52 were assessed. Results. Of 1414 treated PsA and 1164 treated AS patients with samples available for immunogenicity evaluation, 5 (0.35%) and 8 (0.69%), respectively, developed TE-ADA. All but 1 PsA patient were biologic-naive; two of the 5 PsA and one of the 8 AS patients received concomitant methotrexate, and two of the 8 AS patients received concomitant sulfasalazine. Associations between TE-ADA and secukinumab dose, frequency, or administration mode were not observed. Other than one PsA patient, all TE-ADA were non-neutralizing. No TE-ADA were associated with any AE. All TE-ADA were associated with normal secukinumab pharmacokinetics and none were associated with loss of secukinumab efficacy. Conclusion. Secukinumab treatment was associated with a low (< 1%) incidence of immunogenicity in patients with PsA or AS. (clinicaltrials.gov: NCT01392326; NCT01752634; NCT01989468; NCT01358175; NCT01649375; NCT02008916; NCT02159053)

Interleukin-17A blockade with secukinumab results in decreased neutrophil infiltration in psoriasis: minimally-invasive measurement by tape stripping

Psoriasis is a well characterized interleukin (IL)-17A-driven skin disease with neutrophil infiltration and epidermal hyperkeratosis. Several biomarkers, most prominently β-defensin-2 (BD-2), have been identified using local and systemic invasive measurements as responsive markers of IL-17A-driven skin pathology. We sought to determine whether measurements of epidermal proteins by tape stripping could offer a minimally-invasive method to assess treatment responses. We compared the expression of 170 proteins in the epidermis (tape stripping) and dermis (open flow microperfusion) of 8 psoriatic subjects before and after administration of a single dose of subcutaneous (s.c.) antiIL-17A mAb secukinumab. Proteomic analyses of tape strips revealed a >3-fold decrease in 32 epidermal and inflammatory cell proteins in response to secukinumab. The epidermal proteins with the largest (>10-fold) decreases were: matrix metalloproteinase-8 (MMP-8, 15.68-fold, p<0.05); myeloperoxidase (MPO, 14.72-fold, p<0.005); IL-8 (11.93-fold, p<0.05); MMP-9 (10.81-fold, p<0.005); and IL-1β (10.35-fold, p<0.05). For these proteins, greater-fold protein changes were detected in the epidermis compared to dermis. Immunohistochemical analysis confirmed that neutrophils are the predominant cell type in psoriatic skin lesions that express MPO, MMP-8 and MMP-9, and that secukinumab treatment dramatically decreases neutrophil accumulation. Thus, tape stripping may be used to assess epidermal neutrophils, and protein biomarker responses to anti-IL-17A therapy in psoriasis

Global transcriptional response to mammalian temperature provides new insight into Francisella tularensis pathogenesis

<p>Abstract</p> <p>Background</p> <p>After infecting a mammalian host, the facultative intracellular bacterium, <it>Francisella tularensis</it>, encounters an elevated environmental temperature. We hypothesized that this temperature change may regulate genes essential for infection.</p> <p>Results</p> <p>Microarray analysis of <it>F. tularensis </it>LVS shifted from 26°C (environmental) to 37°C (mammalian) showed ~11% of this bacterium's genes were differentially-regulated. Importantly, 40% of the protein-coding genes that were induced at 37°C have been previously implicated in virulence or intracellular growth of <it>Francisella </it>in other studies, associating the bacterial response to this temperature shift with pathogenesis. Forty-four percent of the genes induced at 37°C encode proteins of unknown function, suggesting novel <it>Francisella </it>virulence traits are regulated by mammalian temperature. To explore this possibility, we generated two mutants of loci induced at 37°C [FTL_1581 and FTL_1664 (<it>deoB</it>)]. The FTL_1581 mutant was attenuated in a chicken embryo infection model, which was likely attributable to a defect in survival within macrophages. FTL_1581 encodes a novel hypothetical protein that we suggest naming <it>t</it>emperature-<it>i</it>nduced, <it>v</it>irulence-associated locus <it>A</it>, <it>tivA</it>. Interestingly, the <it>deoB </it>mutant showed diminished entry into mammalian cells compared to wild-type LVS, including primary human macrophages and dendritic cells, the macrophage-like RAW 264.7 line, and non-phagocytic HEK-293 cells. This is the first study identifying a <it>Francisella </it>gene that contributes to uptake into both phagocytic and non-phagocytic host cells.</p> <p>Conclusion</p> <p>Our results provide new insight into mechanisms of <it>Francisella </it>virulence regulation and pathogenesis. <it>F. tularensis </it>LVS undergoes considerable gene expression changes in response to mammalian body temperature. This temperature shift is important for the regulation of genes that are critical for the pathogenesis of <it>Francisella</it>. Importantly, the compilation of temperature-regulated genes also defines a rich collection of novel candidate virulence determinants, including <it>tivA </it>(FTL_1581). An analysis of <it>tivA </it>and <it>deoB </it>(FTL_1664) revealed that these genes contribute to intracellular survival and entry into mammalian cells, respectively.</p

The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery

Contains fulltext : 96401.pdf (publisher's version ) (Open Access

EEG Biofeedback as a Treatment for Substance Use Disorders: Review, Rating of Efficacy, and Recommendations for Further Research

Electroencephalographic (EEG) biofeedback has been employed in substance use disorder (SUD) over the last three decades. The SUD is a complex series of disorders with frequent comorbidities and EEG abnormalities of several types. EEG biofeedback has been employed in conjunction with other therapies and may be useful in enhancing certain outcomes of therapy. Based on published clinical studies and employing efficacy criteria adapted by the Association for Applied Psychophysiology and Biofeedback and the International Society for Neurofeedback and Research, alpha theta training—either alone for alcoholism or in combination with beta training for stimulant and mixed substance abuse and combined with residential treatment programs, is probably efficacious. Considerations of further research design taking these factors into account are discussed and descriptions of contemporary research are given