Valid Paradigm Research Articles

The efficacy of surgical treatment of cancer – 20 years later

IntroductionCancer treatment will be effective only if it is be based on a valid paradigm of what cancer is and therefore capable of affecting the course of the disease. A review in 1993 found no evidence that surgery affected the course of the disease and an alternative paradigm was proposed. A review of mammography screening trials in 1996 found no benefits from breast cancer screening. This was predicted by this alternative paradigm. This review updates the evidence twenty years later. AimTo identify evidence that the primary treatment of cancer, surgery, has been shown to affect the course of the disease.If there is no such evidence, then to identify the correct paradigm of what cancer is from other cancer treatments that have been shown to be effective. MethodBecause surgery has never been shown in a randomised controlled trial to affect the course of cancer seven other indirect methods were used to evaluate its efficacy. ResultsNone of the seven indirect methods used showed that surgery clearly affects the course of the disease for any type of cancer. The lack of benefits from cancer screening now includes not only from breast cancer but also from bowel, lung, prostate and ovarian cancer screening. This confirms that cancer surgery is based on an invalid paradigm of what cancer is. Survival figures following treatments based on an alternative paradigm that assumes cancer is a systemic disease were found to be superior to those following surgery, reinforcing the conclusion that cancer is a systemic disease and that cancer surgery is unlikely to be of benefit in most cases. ConclusionNo benefits can be expected to be achieved from using cancer surgery except in a few immediately life-threatening situations. Surgery appears to be based on an invalid paradigm of what cancer is. Cancer appears to be a systemic disease and therefore standard treatments need to be reassessed in this light.

Validation of satellite sounder environmental data records: Application to the Cross‐track Infrared Microwave Sounder Suite

The Joint Polar Satellite System (JPSS) Cross‐track Infrared Microwave Sounder Suite (CrIMSS) is an advanced operational satellite sounding system concept comprised of the Cross‐track Infrared Sounder and the Advanced Technology Microwave Sounder. These are synergistically designed to retrieve key environmental data records (EDR), namely atmospheric vertical temperature, moisture, and pressure profiles. CrIMSS will serve as the low‐Earth orbit satellite sounding system, starting with the Suomi National Polar‐orbiting Partnership (S‐NPP) satellite and spanning the JPSS‐1 and JPSS‐2 satellites. This paper organizes the general paradigm for validation of atmospheric profile EDR retrieved from satellite nadir sounder systems (e.g., CrIMSS) as a synthesis of complementary methods and statistical assessment metrics. The validation methodology is ordered hierarchically to include global numerical model comparisons, satellite EDR intercomparisons, radiosonde matchup assessments (conventional, dedicated, and reference), and intensive campaign “dissections.” We develop and recommend the proper approach for computing profile statistics relative to correlative data derived from high‐resolution in situ data (viz., radiosondes) reduced to forward model layers. The standard statistical metrics used for EDR product assessments on “coarse layers” are defined along with an overview of water vapor weighting schemes and the use of averaging kernels. We then overview the application of the methodology to CrIMSS within the context of the JPSS calibration/validation program, with focus given to summarizing the core data sets to be used for validation of S‐NPP sounder EDR products.

Increased neural response to peer rejection associated with adolescent depression and pubertal development.

Sensitivity to social evaluation has been proposed as a potential marker or risk factor for depression, and has also been theorized to increase with pubertal maturation. This study utilized an ecologically valid paradigm to test the hypothesis that adolescents with major depressive disorder (MDD) would show altered reactivity to peer rejection and acceptance relative to healthy controls in a network of ventral brain regions implicated in affective processing of social information. A total of 48 adolescents (ages 11-17), including 21 with a current diagnosis of MDD and 27 age- and gender-matched controls, received rigged acceptance and rejection feedback from fictitious peers during a simulated online peer interaction during functional neuroimaging. MDD youth showed increased activation to rejection relative to controls in the bilateral amygdala, subgenual anterior cingulate, left anterior insula and left nucleus accumbens. MDD and healthy youth did not differ in response to acceptance. Youth more advanced in pubertal maturation also showed increased reactivity to rejection in the bilateral amygdala/parahippocampal gyrus and the caudate/subgenual anterior cingulate, and these effects remained significant when controlling for chronological age. Findings suggest that increased reactivity to peer rejection is a normative developmental process associated with pubertal development, but is particularly enhanced among youth with depression.

FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease

Huntington disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved motor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect of FTY720 administration was associated with a significant strengthening of neuronal activity and connectivity and, with reduction of mutant huntingtin aggregates, and it was also paralleled by increased phosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate protein toxicity.

Development of a High-Throughput Screening Paradigm for the Discovery of Small-Molecule Modulators of Adenylyl Cyclase: Identification of an Adenylyl Cyclase 2 Inhibitor

Adenylyl cyclase (AC) isoforms are implicated in several physiologic processes and disease states, but advancements in the therapeutic targeting of AC isoforms have been limited by the lack of potent and isoform-selective small-molecule modulators. The discovery of AC isoform-selective small molecules is expected to facilitate the validation of AC isoforms as therapeutic targets and augment the study of AC isoform function in vivo. Identification of chemical probes for AC2 is particularly important because there are no published genetic deletion studies and few small-molecule modulators. The present report describes the development and implementation of an intact-cell, small-molecule screening approach and subsequent validation paradigm for the discovery of AC2 inhibitors. The NIH clinical collections I and II were screened for inhibitors of AC2 activity using PMA-stimulated cAMP accumulation as a functional readout. Active compounds were subsequently confirmed and validated as direct AC2 inhibitors using orthogonal and counterscreening assays. The screening effort identified SKF-83566 [8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide] as a selective AC2 inhibitor with superior pharmacological properties for selective modulation of AC2 compared with currently available AC inhibitors. The utility of SKF-83566 as a small-molecule probe to study the function of endogenous ACs was demonstrated in C2C12 mouse skeletal muscle cells and human bronchial smooth muscle cells.

The dynamics of cumulative trauma and trauma types in adults patients with psychiatric disorders: Two cross-cultural studies.

There is an intricate divide between three major valid paradigms in studying traumatic processes: The psychiatric paradigm that focused mostly on the survival types of traumas and on posttraumatic ...

Problematising Style Differences Theory and Professional Learning in Educational Psychology

The conceptual basis for a model of professional learning in educational psychology is presented in this article. The approach is one aimed at an integration and application of theories of knowledge management with educational and organisational psychology in a pragmatic research methodology underpinning professional learning. The model focuses upon the idea of praxis and the working ideal of a ‘thinking practitioner’. This is in turn applied to the development of individual differences theory as part of a critical revision problematising theory associated with researching style differences in cognition, learning and management. A need for critical revisionism, new directions in researching style differences and professional education is identified as part of an example illustrating a way to establish valid epistemic change and paradigm shift necessary for this development. The argument underpinning this approach, finally, concludes that the future is very much part of the past, as a knowledge source for informing contemporary professional learning thereby ensuring practice is not stuck in the present.

Flight dynamics, parametric modelling and real-time control of a 1-DOF Tailplane

This article presents aerodynamic modelling and real-time control of a 1-degree-of-freedom free to pitch Tailplane. The system is designed to serve as an experimental test facility for investigating flight dynamics principles, model validation and different feedback control paradigms. A high-fidelity plant model is an important first step in many flight-related applications such as control system design, analyses and pilot training. To achieve these objectives, a detailed study is conducted employing analytical as well as system identification (SI) techniques. Analytical approach although less accurate complements SI process. This synergy is exploited along with statistical and time domain tests to arrive at a high-fidelity model. It is demonstrated that such an integrated approach is suitable for modelling a class of unmanned air vehicles. The SI model is then employed for controller synthesis. Finally, real-time pitch control under stick command is demonstrated utilizing classical proportional integrator control law.

The applied value of collaborative memory research in aging: Behavioral and neural considerations

Our aim in this paper is to bring attention to the applied value of collaborative memory research in aging. At this time, much collaborative memory research focuses on the negative effects of collaboration in younger adults, and is primarily basic in nature. Here, we highlight the positive effects of collaboration that have received less attention, with a particular emphasis on the applied value of these effects in older adults. We first review studies to show that recalling in a group improves later individual recall and reduces memory errors in older adults. We then outline a four-step approach towards bridging laboratory and applied collaborative memory research, which involves: (1) complementing traditional paradigms with more ecologically valid paradigms, (2) evaluating these paradigms in applied settings, (3) adapting these paradigms for use with cognitively intact and cognitively impaired populations, and (4) modifying these paradigms to examine the neural systems that operate during collaborative recall.

Gaze-independent BCI-spelling using rapid serial visual presentation (RSVP)

ObjectiveA Brain Computer Interface (BCI) speller is a communication device, which can be used by patients suffering from neurodegenerative diseases to select symbols in a computer application. For patients unable to overtly fixate the target symbol, it is crucial to develop a speller independent of gaze shifts. In the present online study, we investigated rapid serial visual presentation (RSVP) as a paradigm for mental typewriting. MethodsWe investigated the RSVP speller in three conditions, regarding the Stimulus Onset Asynchrony (SOA) and the use of color features. A vocabulary of 30 symbols was presented one-by-one in a pseudo random sequence at the same location of display. ResultsAll twelve participants were able to successfully operate the RSVP speller. The results show a mean online spelling rate of 1.43symb/min and a mean symbol selection accuracy of 94.8% in the best condition. ConclusionWe conclude that the RSVP is a promising paradigm for BCI spelling and its performance is competitive with the fastest gaze-independent spellers in literature. SignificanceThe RSVP speller does not require gaze shifts towards different target locations and can be operated by non-spatial visual attention, therefore it can be considered as a valid paradigm in applications with patients for impaired oculo-motor control.

Validation of knowledge-based systems: a reassessment of the field

The subject of validation and verification (V&V) of knowledge-based systems (KBS) has been one of decreasing importance in the last decade. Research and development in the field reduced drastically. One of the main reasons is the persistent software challenges and failures. These failures have been categorized in different ways. One initiative however, which most researchers in the field agree upon, is that the only way to eliminate these problems is by rigorously performing V&V. Although there have been vast improvements in the field of V&V methodology, studies indicate that KBS industry still lacks rigorous validation methods. In this paper, we review the most important validation paradigms described in literature for KBS during the years of their fame. Additionally, this article studies the significant methods, aims to reassess these methods in light of recent advances, and propose new future directions for validation of KBS.

CID: a valid incentive delay paradigm for children

Despite several modifications and the wide use of the monetary incentive delay paradigm (MID; Knutson et al. in J Neurosci 21(16):RC159, 2001a) for assessing reward processing, evidence concerning its application in children is scarce. A first child-friendly MID modification has been introduced by Gotlib et al. (Arch Gen Psychiatry 67(4): 380-387, 2010); however, comparability in the results of different tasks and validity across different age groups remains unclear. We investigated the validity of a newly modified MID task for children (CID) using functional magnetic resonance imaging. The CID comprises the integration of a more age appropriate feedback phase. We focused on reward anticipation and their neural correlates. Twenty healthy young adults completed the MID and the CID. Additionally, 10 healthy children completed the CID. As expected, both paradigms elicited significant ventral and dorsal striatal activity in young adults during reward anticipation. No differential effects of the tasks on reaction times, accuracy rates or on the total amount of gain were observed. Furthermore, the CID elicited significant ventral striatal activity in healthy children. In conclusion, these findings demonstrate evidence for the validity of the CID paradigm. The CID can be recommended for the application in future studies on reward processing in children, adolescents, and in adults.

Goodbye International Journal of Andrology, welcome Andrology!

Goodbye <i>International Journal of Andrology</i>, welcome <i>Andrology</i>!

Loss of stress response as a consequence of viral infection: implications for disease and therapy

Herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. Having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. Host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. In the case of Newcastle disease virus, the effects of viral infection on heat shock proteins may be leveraged as a therapy for cancer. Finally, the search for a specific virus being responsible for a condition like chronic fatigue syndrome may not be worthwhile if the disease is simply a nonspecific response to viral infection.

Pitfalls of the parametric approaches exploiting cross-validation for model order selection

Prediction error methods (PEM) are often used to identify a dynamic system starting from input-output samples. In particular, in the classical parametric scenario models of different order are identified from data and compared using the cross validation (CV) paradigm where measurements are split into a training and a validation data set. However, some inefficiencies related to this popular approach to system identification have been recently pointed out. This paper provides some insights on the reasons of such pitfalls, clarifying why PEM equipped with CV may lead to estimators with large variance and a poor predictive capability on new data.

Neuroplasticity in middle age: an ecologically valid approach

A commentary on The effect of leisure activity golf practice on motor imagery: an fMRI study in middle adulthood by Bezzola, L., Merillat, S., and Jancke, L. (2012). Front. Hum. Neurosci. 6:67. doi: 10.3389/fnhum.2012.00067 “You know you're middle aged when caution is the only thing you care to exercise.” In “The effect of leisure activity golf practice on motor imagery: an fMRI study in middle adulthood,” Bezzola et al. (2012) demonstrate changes in the neural representations of imagined movement following 40 h of golf training. An experimental (golf novice) and control group were scanned using functional MRI during kinetic motor imagery of their golf swing both prior to and following the golf training (with the control group matched for average pre- to post-test duration). The authors found reductions in bilateral dorsal premotor cortex activity during motor imagery following the training period only in the experimental group and not the control group, suggesting more efficient neural representations following training. This study is unique among the large number of papers that have been published in recent years on experience-dependent sensorimotor neuroplasticity. One defining feature of this work is that the characteristics of the training program were not regulated. The experimental group simply participated in golf training for a total of 40 h. This ecologically valid approach makes the findings generalizable to what individuals may choose to do for their own leisure and exercise on any given day. This indicates that precisely regimented training programs are not de rigueur for behavioral and brain plasticity to occur. Secondly, the participants ranged in age from 40 to 60 years. Research on the cognitive neuroscience of aging has begun to yield insights into age differences in motor control and learning at both the behavioral and brain levels (cf. Seidler et al., 2010). However, work with individuals in the middle aged range of the lifespan is scant. It is important to investigate both behavioral and neural plasticity within this age range, however, because these individuals make up a large portion of the workforce. Moreover, such an approach will be critical for identifying trajectories of decline. The few studies that have investigated behavioral and brain function of participants in this age range have yielded the sobering finding that many changes evident in older adults are already manifest at this point. For example, individuals aged 40–60-years old exhibit evidence of declines in sensorimotor adaptation in comparison to those in their twenties (Heuer and Hegele, 2011). Interestingly, retention of the ability to transfer learning to new conditions is preserved (Heuer and Hegele, 2011), similar to what has also been reported in older individuals (Seidler, 2007; Langan and Seidler, 2011). Likewise, numerous studies have shown that older adults tend to under-recruit task relevant brain regions while over-activating additional areas in comparison to young adults (Langan et al., 2010; Seidler et al., 2010). Different theories exist regarding the function of this over-activation (cf. Lindenberger et al., 2012), including the compensation viewpoint and the nonselective recruitment or dedifferentiation view. The compensation view posits that this over-recruitment serves to compensate for age-related brain structural and biochemical declines and is associated with better performance (cf. Reuter-Lorenz and Lustig, 2005). In contrast, dedifferentiation suggests that over-recruitment is a sign of less efficient or specific neural representations with age (Li and Lindenberger, 1999). Recent findings support the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), which posits that older adults reach their limits of cognitive and neural resources at lower levels of task difficulty (Reuter-Lorenz and Cappell, 2008; Carp et al., 2010; Schneider-Garces et al., 2010). That is, they exhibit over-activation as a compensatory mechanism at lower levels of task difficulty, and once they have reached their maximum capacity then activation declines. Functional brain over-activation is already apparent in individuals that are 60-years old (Burgmans et al., 2010). Moreover, studies investigating brain volumetric changes with age indicate that losses are evident in those within the range of 40–60-years old, particularly for brain structures involved in learning and memory (Ziegler et al., 2012). Thus, although behavioral changes may not be as marked in middle aged individuals as they are in older adults, brain structure and function are exhibiting evidence of age differences. United States Census data predict that there will be 88.5 million people in the US over the age of 65 by the year 2050. This dramatic shift in the population will increase the need for programs and interventions that can facilitate activities of daily living for older adults. Further investigation of neuroplastic changes within middle aged individuals will be important for providing prescriptions regarding the optimal time point for motor training interventions. Bezzola et al. (2012) have gotten us onto the fairway by providing evidence for neuroplastic changes in middle aged adults using a realistic and ecologically valid paradigm.

Physician Brain Drain from Sub-Saharan Africa: Exploring the Utility of an Eco-psychopolitical Validity Framework for Medical Migration Research

Abstract In-depth understanding of any critical social issue requires investigators to use analytical tools that reflect the complexity of the social issue of interest. Toward this aim, I examine the medical brain drain from Sub-Saharan Africa to the United States through the lens of the eco-psychopolitical validity model (see, Christen & Perkins, 2008; Prilleltensky, 2008), an integrative approach that stresses the combined influences of structural factors, individual agency, and power at play in human dynamics and social systems. By adapting the eco-psychopolitical validity model to the study of medical skilled migration, I construe migration as a liberating venture articulated around the triadic process of oppression, empowerment, and wellness. If migrants yearn to breathe free, then emigre physicians are essentially in pursuit of liberation and wellbeing. However, in a world of profound health disparities, where the increasing emigration of medical doctors from resource-constrained countries ultimately leads to loss of lives in the communities left behind, migrant doctors’ individual agency and the multilevel contexts that enable or constrain them to emigrate require critical reflection. Some emerging themes and variations of an ongoing qualitative study are examined using the eco-psychopolitical validity paradigm.

Relevance of computational rock physics

To validate the transport (fluid and electrical) and elastic properties computed on CT scan pore-scale volumes of natural rock, we first contrast these values to physical laboratory measurements. We find that computational and physical data obtained on the same rock material source often differ from each other. This mismatch, however, does not preclude the validity of either of the data type — it only implies that expecting a direct match between the effective properties of two volumes of very different sizes taken from the same heterogeneous material is generally incorrect. To address this situation, instead of directly comparing data points generated by different methods of measurement, we compare trends formed by such data points. These trends include permeability versus porosity; electrical formation factor versus porosity; and elastic moduli (elastic-wave velocity) versus porosity. In the physical laboratory, these trends are generated by measuring a significant number of samples. In contrast, in the computational laboratory, these trends are often hidden inside a very small digital sample and can be derived by subsampling it. Hence, we base our validation paradigm on the assumption that if these computational trends match relevant physical trends and/or theoretical rock physics transforms, the computational results are correct. We present examples of such validation for clastic and carbonate samples, including drill cuttings.

Uncertainty estimation with a finite dataset in the assessment of classification models

To successfully translate genomic classifiers to the clinical practice, it is essential to obtain reliable and reproducible measurement of the classifier performance. A point estimate of the classifier performance has to be accompanied with a measure of its uncertainty. In general, this uncertainty arises from both the finite size of the training set and the finite size of the testing set. The training variability is a measure of classifier stability and is particularly important when the training sample size is small. Methods have been developed for estimating such variability for the performance metric AUC (area under the ROC curve) under two paradigms: a smoothed cross-validation paradigm and an independent validation paradigm. The methodology is demonstrated on three clinical microarray datasets in the microarray quality control consortium phase two project (MAQC-II): breast cancer, multiple myeloma, and neuroblastoma. The results show that the classifier performance is associated with large variability and the estimated performance may change dramatically on different datasets. Moreover, the training variability is found to be of the same order as the testing variability for the datasets and models considered. In conclusion, the feasibility of quantifying both training and testing variability of classifier performance is demonstrated on finite real-world datasets. The large variability of the performance estimates shows that patient sample size is still the bottleneck of the microarray problem and the training variability is not negligible.

Towards an integrated model of practice evaluation balancing accountability, critical knowledge and developmental perspectives

Against a backdrop of economic globalisation, where welfare practitioners find themselves caught between modernising policy reform and demanding practice realities, there is an urgent need to rethink the relationship between research, evaluation and professional practice. In this article three perspectives concerned with accountability, critical knowledge production and development will be examined as a basis for understanding the different methodological discourses on evaluation. The debate between evidence-based practice (EBP) and critical practice (CP) is deployed to highlight a choice facing both the practitioner and researcher between producing two competing kinds of knowledge for practice. The former is based upon technical know how and skills that may be equated with a ‘search for certainty’ and found increasingly in technocratic systems of accountability; whilst the latter is concerned with critical exploration and development in promoting more emancipatory forms of practice that may be equated with the ‘creative use of uncertainty’. Drawing on practice examples and research from the field of mental health, it is argued that balancing accountability, critical knowledge production and development offers a valid paradigm for achieving effective practice evaluation alongside a broader commitment to social justice.