3-year results of docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer: a pilot study.

BACKGROUND: Docetaxel has proven efficacy in metastatic breast cancer. In this pilot study, we explored the efficacy/feasibility of docetaxel-based sequential and combination regimens as adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: From March 1996 till March 1998, four consecutive groups of patients with stages II and III breast cancer, aged < or = 70 years, received one of the following regimens: a) sequential Doxorubicin (A) --> Docetaxel (T) --> CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil): A 75 mg/m q 3 wks x 3, followed by T100 mg/m2 q 3 wks x 3, followed by i.v. CMF Days 1+8 q 4 wks x 3; b) sequential accelerated A --> T --> CMF: A and T administered at the same doses q 2 wks with Lenograstin support; c) combination therapy: A 50 mg/m2 + T 75 mg/m2 q 3 wks x 4, followed by CMF x 4; d) sequential T --> A --> CMF: T and A, administered as in group a), with the reverse sequence. When indicated, radiotherapy was administered during or after CMF, and Tamoxifen after CMF. RESULTS: Ninety-three patients were treated. The median age was 48 years (29-66) and the median number of positive axillary nodes was 6 (1-25). Tumors were operable in 94% and locally advanced in 6% of cases. Pathological tumor size was >2 cm in 72% of cases. There were 21 relapses, (18 systemic, 3 locoregional) and 11 patients (12%) have died from disease progression. At median follow-up of 39 months (6-57), overall survival (OS) was 87% (95% CI, 79-94%) and disease-free survival (DFS) was 76% (95% CI, 67%-85%). CONCLUSION: The efficacy of these docetaxel-based regimens, in terms of OS and DFS, appears to be at least as good as standard anthracycline-based adjuvant chemotherapy (CT), in similar high-risk patient populations.

Sequential anomaly detection in the presence of noise and limited feedback

This paper describes a methodology for detecting anomalies from sequentially observed and potentially noisy data. The proposed approach consists of two main elements: 1) filtering, or assigning a belief or likelihood to each successive measurement based upon our ability to predict it from previous noisy observations and 2) hedging, or flagging potential anomalies by comparing the current belief against a time-varying and data-adaptive threshold. The threshold is adjusted based on the available feedback from an end user. Our algorithms, which combine universal prediction with recent work on online convex programming, do not require computing posterior distributions given all current observations and involve simple primal-dual parameter updates. At the heart of the proposed approach lie exponential-family models which can be used in a wide variety of contexts and applications, and which yield methods that achieve sublinear per-round regret against both static and slowly varying product distributions with marginals drawn from the same exponential family. Moreover, the regret against static distributions coincides with the minimax value of the corresponding online strongly convex game. We also prove bounds on the number of mistakes made during the hedging step relative to the best offline choice of the threshold with access to all estimated beliefs and feedback signals. We validate the theory on synthetic data drawn from a time-varying distribution over binary vectors of high dimensionality, as well as on the Enron email dataset. © 1963-2012 IEEE.

Adaptive Mixture Modelling Metropolis Methods for Bayesian Analysis of Non-linear State-Space Models.

We describe a strategy for Markov chain Monte Carlo analysis of non-linear, non-Gaussian state-space models involving batch analysis for inference on dynamic, latent state variables and fixed model parameters. The key innovation is a Metropolis-Hastings method for the time series of state variables based on sequential approximation of filtering and smoothing densities using normal mixtures. These mixtures are propagated through the non-linearities using an accurate, local mixture approximation method, and we use a regenerating procedure to deal with potential degeneracy of mixture components. This provides accurate, direct approximations to sequential filtering and retrospective smoothing distributions, and hence a useful construction of global Metropolis proposal distributions for simulation of posteriors for the set of states. This analysis is embedded within a Gibbs sampler to include uncertain fixed parameters. We give an example motivated by an application in systems biology. Supplemental materials provide an example based on a stochastic volatility model as well as MATLAB code.

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies.

Nested heuristic methods for the location-routeing problem

The concept of 'nested methods' is adopted to solve the location-routeing problem. Unlike the sequential and iterative approaches, in this method we treat the routeing element as a sub-problem within the larger problem of location. Efficient techniques that take into account the above concept and which use a neighbourhood structure inspired from computational geometry are presented. A simple version of tabu search is also embedded into our methods to improve the solutions further. Computational testing is carried out on five sets of problems of 400 customers with five levels of depot fixed costs, and the results obtained are encouraging.

Scheduling batches with sequential job processing for two-machine flow and open shops

In this paper, we study a problem of scheduling and batching on two machines in a flow-shop and open-shop environment. Each machine processes operations in batches, and the processing time of a batch is the sum of the processing times of the operations in that batch. A setup time, which depends only on the machine, is required before a batch is processed on a machine, and all jobs in a batch remain at the machine until the entire batch is processed. The aim is to make batching and sequencing decisions, which specify a partition of the jobs into batches on each machine, and a processing order of the batches on each machine, respectively, so that the makespan is minimized. The flow-shop problem is shown to be strongly NP-hard. We demonstrate that there is an optimal solution with the same batches on the two machines; we refer to these as consistent batches. A heuristic is developed that selects the best schedule among several with one, two, or three consistent batches, and is shown to have a worst-case performance ratio of 4/3. For the open-shop, we show that the problem is NP-hard in the ordinary sense. By proving the existence of an optimal solution with one, two or three consistent batches, a close relationship is established with the problem of scheduling two or three identical parallel machines to minimize the makespan. This allows a pseudo-polynomial algorithm to be derived, and various heuristic methods to be suggested.

Contingent screening for down syndrome is an efficient alternative to non-disclosure sequential screening

Objective To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening (the Integrated test), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. Methods Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. Results Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. Conclusion Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Computationally efficient sequential learning algorithms for direct link resource-allocating networks

Computionally efficient sequential learning algorithms are developed for direct-link resource-allocating networks (DRANs). These are achieved by decomposing existing recursive training algorithms on a layer by layer and neuron by neuron basis. This allows network weights to be updated in an efficient parallel manner and facilitates the implementation of minimal update extensions that yield a significant reduction in computation load per iteration compared to existing sequential learning methods employed in resource-allocation network (RAN) and minimal RAN (MRAN) approaches. The new algorithms, which also incorporate a pruning strategy to control network growth, are evaluated on three different system identification benchmark problems and shown to outperform existing methods both in terms of training error convergence and computational efficiency. (c) 2005 Elsevier B.V. All rights reserved.

Ecological coherence in marine reserve network design: an empirical evaluation of sequential site selection using genetic structure

Ecological coherence is a multifaceted conservation objective that includes some potentially conflicting concepts. These concepts include the extent to which the network maximises diversity (including genetic diversity) and the extent to which protected areas interact with non-reserve locations. To examine the consequences of different selection criteria, the preferred location to complement protected sites was examined using samples taken from four locations around each of two marine protected areas: Strangford Lough and Lough Hyne, Ireland. Three different measures of genetic distance were used: FST, Dest and a measure of allelic dissimilarity, along with a direct assessment of the total number of alleles in different candidate networks. Standardized site scores were used for comparisons across methods and selection criteria. The average score for Castlehaven, a site relatively close to Lough Hyne, was highest, implying that this site would capture the most genetic diversity while ensuring highest degree of interaction between protected and unprotected sites. Patterns around Strangford Lough were more ambiguous, potentially reflecting the weaker genetic structure around this protected area in comparison to Lough Hyne. Similar patterns were found across species with different dispersal capacities, indicating that methods based on genetic distance could be used to help maximise ecological coherence in reserve networks. ⺠Ecological coherence is a key component of marine protected area network design. ⺠Coherence contains a number of competing concepts. ⺠Genetic information from field populations can help guide assessments of coherence. ⺠Average choice across different concepts of coherence was consistent among species. ⺠Measures can be combined to compare the coherence of different network designs.

A mixed methods study of the work patterns of full-time nurse practitioners in nursing homes

Aims and objectives: The aim of this study was to explore the integration of the nurse practitioner role in Canadian nursing homes to enable its full potential to be realised for resident and family care. The objective was to determine nurse practitioners' patterns of work activities. 

Background: Nurse practitioners were introduced in Canadian nursing homes a decade ago on a pilot basis. In recent years, government and nursing home sector interest in the role has grown along with the need for data to inform planning efforts. 

Design: The study used a sequential mixed methods design using a national survey followed by case studies. 

Methods: A national survey of nurse practitioners included demographic items and the EverCare Nurse Practitioner Role and Activity Scale. Following the survey, case studies were conducted in four nursing homes. Data were collected using individual and focus group interviews, document reviews and field notes. 

Results: Twenty-three of a target population of 26 nurse practitioners responded to the survey, two-thirds of whom provided services in nursing homes with one site and the remainder in nursing homes with as many as four sites. On average, nurse practitioners performed activities in communicator, clinician, care manager/coordinator and coach/educator subscales at least three to four times per week and activities in the collaborator subscale once a week. Of the 43 activities, nurse practitioners performed daily, most were in the clinician and communicator subscales. Case study interviews involved 150 participants. Findings complemented those of the survey and identified additional leadership activities. 

Conclusion: Nurse practitioners undertake a range of primary health care and advanced practice activities which they adapt to meet the unique needs of nursing homes. Relevance to clinical practice: Knowledge of work patterns enables nursing homes to implement the full range of nurse practitioner roles and activities to enhance resident and family care.

Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer

AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients.

PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks.

RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy.

CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

k-fold Subsampling based Sequential Backward Feature Elimination

We present a new wrapper feature selection algorithm for human detection. This algorithm is a hybrid featureselection approach combining the benefits of filter and wrapper methods. It allows the selection of an optimalfeature vector that well represents the shapes of the subjects in the images. In detail, the proposed featureselection algorithm adopts the k-fold subsampling and sequential backward elimination approach, while thestandard linear support vector machine (SVM) is used as the classifier for human detection. We apply theproposed algorithm to the publicly accessible INRIA and ETH pedestrian full image datasets with the PASCALVOC evaluation criteria. Compared to other state of the arts algorithms, our feature selection based approachcan improve the detection speed of the SVM classifier by over 50% with up to 2% better detection accuracy.Our algorithm also outperforms the equivalent systems introduced in the deformable part model approach witharound 9% improvement in the detection accuracy

A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

Sediment metal bioavailability in Lake Taihu, China: evaluation of sequential extraction, DGT, and PBET techniques

The European “Community Bureau of Reference” (BCR) sequential extraction procedure, diffusive gradient in thin-films technique (DGT), and physiologically based extraction test were applied to assess metal bioavailability in sediments of Lake Taihu (n = 13). Findings from the three methods showed that Cd was a significant problem in the western lake whereas Cu, Zn, and Ni pollution was most severe in the northern lake. Results from the sequential extraction revealed that more than 50 % of the Cu and Zn were highly mobile and defined within the extractable fraction (AS1 + FM2 + OS3) in the majority of the sediments, in contrast extractable fractions of Ni and Cd were lower than 50 % in most of the sampling sites. Average Cu, Zn, Ni, and Cd bioaccessibilities were <50 % in the gastric phase. Zn and Cd bioaccessibility in the intestinal phase was ∼50 % lower than the gastric phase while bioaccessibilities of Cu and Ni were 47–57 % greater than the gastric phase. Linear regression analysis between DGT and BCR measurements indicated that the extractable fractions (AS1 + FM2 + OS3) in the reducing environment were the main source of DGT uptake, suggesting that DGT is a good in situ evaluation tool for metal bioavailability in sediments.

The effectiveness of peer mentoring in promoting a positive transition to higher education for first-year undergraduate students: a mixed methods systematic review protocol

Background: The global transfer of nursing and midwifery education to higher education institutes has led to student nurses and midwives experiencing challenges previously faced by traditional third-level students, including isolation, loneliness, financial difficulties and academic pressure. These challenges can contribute to increased stress and anxiety levels which may be detrimental to the successful transition to higher education, thus leading to an increase in attrition rates. Peer mentoring as an intervention has been suggested to be effective in supporting students in the transition to third-level education through enhancing a sense of belongingness and improving student satisfaction, engagement and retention rates. This proposed systematic review aims to determine the effectiveness of peer mentoring in enhancing levels of student engagement, sense of belonging and overall satisfaction of first-year undergraduate students following transition into higher education.
Methods: MEDLINE, Web of Knowledge, ProQuest, Embase, CINAHL, ERIC, PsycINFO and CENTRAL databases will be searched for qualitative, quantitative and mixed methods studies on the implementation of peer assessment strategies in higher education institutes (HEIs) or universities for full-time, first-year adult students (>17 years). Included studies will be limited to the English language. The quality of included studies will be assessed using a validated Mixed Methods Appraisal Tool (MMAT). The findings will be presented as a narrative synthesis or meta-analysis as appropriate following sequential explanatory synthesis.
Discussion: The review will provide clear, non-biased evidence-based guidance to all third-level educators on the effectiveness of peer-mentoring programmes for first-year undergraduates. The review is necessary to help establish which type of peer mentoring is most effective. The evidence from qualitative and quantitative studies drawn from the international literature will be utilised to illustrate the best way to implement and evaluate peer mentoring as an effective intervention and will be useful in guiding future research and practice in this area. These findings may be applied internationally across all disciplines.