The Role of Thyroid Hormone in the Ventromedial Nucleus of the Hypothalamus

The hypothalamic arcuate and paraventricular nuclei play important roles in the neuroendocrine regulation of systemic thyroid hormone homeostasis. However, the roles of other hypothalamic regions are poorly understood. Triiodothyronine (T3) is the active form of thyroid hormone. T3 administration to the hypothalamic ventromedial nucleus (VMN) of rats stimulates feeding, although the mechanism remains unclear. Activation and inactivation of thyroid hormones is mediated by the iodothyonine deiodinases, where D2 is the activating enzyme and D3 the inactivating enzyme. Recombinant adeno-associated virus (rAAV) vectors were designed to modulate the local activity of thyroid hormones by over-expressing D2 (rAAV-D2) or D3 (rAAV-D3). Two initial investigations were carried out employing these viruses in vivo. Initially, rats received bilateral injections of either rAAV-D2 or rAAV-GFP into the VMN. Cumulative food intake and body weight were unaffected, despite a significant increase D2 enzyme activity. However, fasted rAAV-D2 treated rats consumed significantly more food than controls over the initial 2 hours of refeeding following a 12 fast. In the second investigation, rats received bilateral injections of either rAAV-D3 or rAAV-GFP into the VMN. Hypothalamic D3 mRNA and brown adipose tissue activity were both significantly increased in the rAAV-D3 group, which was not associated with any change in systemic thyroid hormone levels. This suggested that sympathetic activity had been increased, independent of peripheral thyroid status. In a final investigation, rats were challenged with a high fat diet (HFD) 17 days after iVMN injection of either rAAV-D3 or rAAV-GFP. The rAAV-D3 treated group gained significantly more weight and consumed significantly more energy than controls, per day of HFD treatment. The increased HFD consumption was matched with a significant increase in hypothalamic fatty acid synthase mRNA. This thesis highlights putative mechanisms by which thyroid hormones affect peripheral metabolism and appetite via the VMN, through interplay with neuronal fatty acid homeostasis

The effectiveness of refactoring, based on a compatibility testing taxonomy and a dependency graph

In this paper, we describe and then appraise a testing taxonomy proposed by van Deursen and Moonen (VD&M) based on the post-refactoring repeatability of tests. Four categories of refactoring are identified by VD&M ranging from semantic-preserving to incompatible, where, for the former, no new tests are required and for the latter, a completely new test set has to be developed. In our appraisal of the taxonomy, we heavily stress the need for the inter-dependence of the refactoring categories to be considered when making refactoring decisions and we base that need on a refactoring dependency graph developed as part of the research. We demonstrate that while incompatible refactorings may be harmful and time-consuming from a testing perspective, semantic-preserving refactorings can have equally unpleasant hidden ramifications despite their advantages. In fact, refactorings which fall into neither category have the most interesting properties. We support our results with empirical refactoring data drawn from seven Java open-source systems (OSS) and from the same analysis form a tentative categorization of code smells

The effect of individual difference on learning performance using web-based instruction

Web-Based Instruction (WBI) brings a number of benefits to individuals requiring a combination of specific learning patterns and program structure. In this paper, we propose a WBI program which suits individual differences through an existing framework and which facilitates learning by accommodating learner preferences. In particular, we make advances in three key aspects. Firstly, we study three important individual differences (gender, cognitive style and prior knowledge) as well as their interactions in the resulting learning performances. Secondly, we combined three attributes to measure performance (gain score, number of visited pages and time spent on these pages) of the three interacting individual differences. Thirdly, we in-vestigate system features (navigation tools, additional support and content structure) to see how they can help users acquire information to meet their individual needs, resulting in an improvement in the learning performance. Two studies are presented; in one, we compare results from our program with previous studies thus evaluating its design. In the other, a data mining approach is used to investigate the effect of individual differences and how that could influence learner performance. Results indicate that performance can be affected by individual differences’ behaviour. Additionally, we found that the relationship between individual differences had an even higher impact on learners’ performance. The combined performance measurement attributes give a better understanding of how learners performed

Defining the Domain of Geriatric Medicine in an Urban Public Health System Affiliated with an Academic Medical Center

The American Geriatrics Society has recommended a reexamination of the roles and deployment of providers with expertise in geriatric medicine. Healthcare systems use a variety of strategies to maximize their geriatric expertise. In general, these health systems tend to focus geriatric medicine resources on a group of older adults that are locally defined as the most in need. This article describes a model of care within an academic urban public health system and describes how local characteristics interact to define the domain of geriatric medicine. This domain is defined using 4 years of data from an electronic medical record combined with data collected from clinical trials. From January 2002 to December 2005, 31,443 adults aged 65 and older were seen at any clinical site within this healthcare system. The mean age was 75 (range 65–105); 61% were women; 35% African American, and 2% Hispanic. The payer mix was 80% Medicare and 17% Medicaid. The local geriatric medicine program includes sites of care in inpatient, ambulatory, nursing home, and home-based settings. By design, this geriatric medicine clinical practice complements the care provided to older adults by the primary care practice. Primary care physicians tend to cede care to geriatric medicine for older adults with advanced disability or geriatric syndromes. This is most apparent for older adults in nursing facilities or those requiring home-based care. There is a dynamic interplay between design features, reputation, and capacity that modulates volume, location, and type of patients seen by geriatrics

A framework for the simulation of structural software evolution

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 ACM.As functionality is added to an aging piece of software, its original design and structure will tend to erode. This can lead to high coupling, low cohesion and other undesirable effects associated with spaghetti architectures. The underlying forces that cause such degradation have been the subject of much research. However, progress in this field is slow, as its complexity makes it difficult to isolate the causal flows leading to these effects. This is further complicated by the difficulty of generating enough empirical data, in sufficient quantity, and attributing such data to specific points in the causal chain. This article describes a framework for simulating the structural evolution of software. A complete simulation model is built by incrementally adding modules to the framework, each of which contributes an individual evolutionary effect. These effects are then combined to form a multifaceted simulation that evolves a fictitious code base in a manner approximating real-world behavior. We describe the underlying principles and structures of our framework from a theoretical and user perspective; a validation of a simple set of evolutionary parameters is then provided and three empirical software studies generated from open-source software (OSS) are used to support claims and generated results. The research illustrates how simulation can be used to investigate a complex and under-researched area of the development cycle. It also shows the value of incorporating certain human traits into a simulation—factors that, in real-world system development, can significantly influence evolutionary structures

Powering lights with piezoelectric energy harvesting floors

The present work introduces a new technology for converting energy from steps into electricity. It starts with a study of the mechanical energy available from steps in a busy corridor. The subsequent development efforts and devices are presented, with an iterative approach to prototyping. Methods for enhancing the piezoelectric conversion efficiency have been determined as a part of the process and are introduced in the present article. Capitalizing on these findings, we have fabricated energy-harvesting devices for stairs that power embedded emergency lighting. The typical working unit comprises an energy-harvesting stair nosing, a power management circuit, and an embedded light-emitting diode that lights the tread in front of the user with an illuminance corresponding to emergency standards. The stair nosing generates up to 17.7 mJ of useful electrical energy per activation to provide up to 10.6 seconds of light. The corresponding energy density is 0.49 J per meter square and per step, with an 8.5 mm thick active layer

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

Implementing GRACE Team Care in a Veterans Affairs Medical Center: Lessons Learned and Impacts Observed

In a randomized clinical trial, Geriatric Resources for Assessment and Care of Elders (GRACE), a model of care that works in collaboration with primary care providers (PCPs) and patient-centered medical homes to provide home-based geriatric care management focusing on geriatric syndromes and psychosocial problems commonly found in older adults, improved care quality and reduced acute care use for high-risk, low-income older adults. To assess the effect of GRACE at a Veterans Affairs (VA) Medical Center (VAMC), veterans aged 65 and older from Marion County, Indiana, with PCPs from four of five VAMC clinics who were not on hospice or dialysis were enrolled in GRACE after discharge home from an acute hospitalization. After an initial home-based transition visit to GRACE enrollees, the GRACE team returned to conduct a geriatric assessment. Guided by 12 protocols and input from an interdisciplinary panel and the PCP, the GRACE team developed and implemented a veteran-centric care plan. Hospitalized veterans from the fifth clinic, who otherwise met enrollment criteria, served as a usual-care comparison group. Demographic, comorbidity, and usage data were drawn from VA databases. The GRACE and comparison groups were similar in age, sex, and burden of comorbidity, although predicted risk of 1-year mortality in GRACE veterans was higher. Even so, GRACE enrollment was associated with 7.1% fewer emergency department visits, 14.8% fewer 30-day readmissions, 37.9% fewer hospital admissions, and 28.5% fewer total bed days of care, saving the VAMC an estimated $200,000 per year after program costs during the study for the 179 veterans enrolled in GRACE. Having engaged, enthusiastic VA leadership and GRACE staff; aligning closely with the medical home; and accommodating patient acuity were among the important lessons learned during implementation

His Dream of Passion: Reflections on the work of Lee Strasberg and his influence on British Actor Training (Part Two)

A previous article for Stanislavski Studies (Vol. 4, No 1, 47-62) explored and examined the impact of Lee Strasberg’s Emotion Memory technique and assessed its influence on contemporary approaches to British actor training. This second ‘companion’ article reflects on a much broader range of Strasbergian training techniques in order, initially, to examine their efficacy and to highlight the extent to which they have been absorbed and adapted by acting teachers working in a British training context. Often viewed as a controversial figure - both in the United Kingdom and in the United States - Strasberg’s approach has frequently been vilified and dismissed. This is particularly true of his interpretation of Stanislavski’s Emotion Memory technique. Whereas the earlier article sought to arrive at an informed and balanced view of his deployment of this technique, what follows is an attempt to review other aspects of Strasberg’s work so as to evaluate the coherence and credibility of the assumptions on which his approach was based and to test whether his work remains appropriate and viable in British training environments today. His work on Relaxation, Concentration and Sense Memory will be examined alongside his development of the Private Moment, Song and Dance and Animal exercises. What, if anything, can we learn from Strasberg’s Method-based approach to actor training and how might we begin to consider the impact and unity of his work as a whole as opposed to focusing almost exclusively on his early work on Emotion Memory