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Results for “Paradigm shift”

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PubMed2026

Interpreting cancer genetics through a two-step "evolutionary cascade hypothesis": bridging neutral and selective perspectives.

BACKGROUND: DNA mutations are the fundamental engines of cancer, driving its initiation and progression. The forces that fuel malignancy are also the architects of evolution, shaping life through genetic variations. Mutations, in fact, can emerge naturally from endogenous processes, such as oxidative DNA damage or errors in replication, as well as induced by external factors, including cosmic radiation and chemical carcinogens. MAIN BODY: A key question in cancer research is whether tumor evolution is primarily governed by selective bottlenecks, neutral evolution, or dynamic genetic plasticity. In this work, we examine cancer as a disease driven by evolutionary processes rooted in fundamental biological requirements, including sustained proliferation and nutrient utilization. We hypothesize that the accumulation of mutations activates an evolutionary switch, enabling tumor cells to acquire an enhanced capacity for survival, adaptation, and growth at rates far exceeding typical evolutionary timescales. We propose the "evolutionary cascade hypothesis," a unifying framework that integrates these models into a coherent sequence. At its core lies the failure of DNA repair mechanisms, representing a critical transition in cancer progression. This shift marks the transition from an initial non-Darwinian, neutral phase to a Darwinian, more deterministic phase. CONCLUSIONS: As predictive models of tumor evolution advance through genomic big data and artificial intelligence-driven analysis, the future of cancer treatment may extend beyond targeting individual mutations to disrupting the underlying evolutionary mechanisms that sustain malignancy. This paradigm shift could redefine therapeutic strategies and ultimately improve patient outcomes.

Humans↗

PubMed2004

Bioprosthetic heart valves: the need for a quantum leap.

More than 250,000 bioprosthetic heart valves are being implanted annually. Although the majority of recipients are elderly developed-world patients, the most urgent need for tissue valves is in younger patients, where rapid degeneration of contemporary prostheses remains a serious obstacle. After decades of empirical and mostly futile attempts to extend the longevity of tissue valve prostheses, new insights and solutions are on the horizon. Aetiologically, a shift of focus from mineralization to immune responses and inflammation emerges. On the development side, new engineering approaches to both selective extraction of tissue components and cross-links are increasingly defining the new direction. In order to dramatically improve the performance of bioprosthetic heart valves, these new developments need to lead to a broad consensus for a paradigm shift in a hitherto rather stagnant field of medical research.

Animals↗

PubMedDate not supplied

Spitting into the wind: the irony of treating chronic disease.

OBJECTIVE: To propose a paradigm shift in the role of the pharmacist by encouraging pharmacists' involvement in the achievement and maintenance of healthy lifestyles in their patients, thus reducing the need for long-term medications. DATA SOURCES: Peer-reviewed medical literature, contemporary lay literature, news releases from health organizations/associations, United States health standards, and professional experiences of the authors. SUMMARY: Our current paradigm for the management of chronic disease is malaligned. The medications we use are helpful for many patients with chronic disorders, but they are not curative and leave many individuals with unwanted adverse effects that are often treated with additional medication. The more effective approach to managing many patients with chronic diseases induced through unhealthy lifestyles would be to eat properly, exercise to maintain ideal body weight, and abstain from harmful substances. Managing the root causes of chronic disease would eliminate most of the unhealthy consequences and perhaps reduce the need for long-term medication. Pharmacists have the knowledge and capacity to assist in this endeavor. CONCLUSION: Influencing patients to achieve ideal body weight through proper diet and exercise, encouraging people to stay well, and then helping them to keep well are roles for the pharmacist. If pharmacists made wellness and disease prevention part of their practices, they would have greater impact on improving patients' overall health. Without treating the primary cause of a condition and only treating the symptoms of unhealthy lifestyles, we are in many ways "spitting into the wind."

Chronic Disease↗

PubMed1998

Reflections on evaluative research in audiological rehabilitation.

Changes in service delivery triggered by current conceptualizations of rehabilitation require an accompanying paradigm shift in the approaches used to evaluate the effectiveness of intervention programs in audiological rehabilitation. The present article outlines three fundamental principles of contemporary rehabilitative audiology that have implications concerning the way that audiological rehabilitation services should be conceived and dispensed, as well as the way in which comprehensive evaluative research investigations should be designed and conducted. Traditional treatment efficacy paradigms used to assess the effectiveness of intervention programs in rehabilitative audiology are critiqued. Finally, factors that should guide the development of comprehensive evaluative research paradigms which are consistent with current models of intervention in audiological rehabilitation are outlined.

Correction of Hearing Impairment↗

PubMed1990

Major mental illness, housing, and supports. The promise of community integration.

Providing housing and supports for people with psychiatric disabilities, particularly those who are homeless, is a major public policy challenge. This article summarizes the ways in which the concept of these needs is rapidly shifting in the mental health field. The article is based on research on the effectiveness of non-facility-based community support and rehabilitation approaches, the findings of other disability fields, and the emergence of mental health consumers' own preferences for expanded choices, normal housing, and more responsive services, including consumer-operated services. These new sources of knowledge are facilitating a paradigm shift in which people with psychiatric disabilities are no longer seen as hopeless, or merely as service recipients, but rather as citizens with a capacity for full community participation and integration.

Community Mental Health Services↗

PubMed2026

Repair and regeneration across the lifespan: an ontogenetic perspective.

The capacity for tissue repair and regeneration undergoes a profound and progressive decline across the human lifespan, representing a fundamental driver of aging and chronic disease. This review establishes a comprehensive ontogenetic framework by mapping the continuous biological transition from the flawless, scarless regenerative plasticity of embryonic development to the irreversible fibrotic scarring and organ failure characteristic of senescence. We synthesize the hierarchical collapse of reparative networks across multiple biological scales. Importantly, this ontogenetic decline should not be interpreted as a purely degenerative trajectory but rather as a dynamic systems-level reprogramming in which evolutionary trade-offs prioritize tumor suppression, immune surveillance, and reproductive fitness over long-term regenerative fidelity. Recognizing this adaptive reallocation of biological resources reframes aging not simply as failure but as a predictable recalibration of repair hierarchies. At the molecular and cellular levels, the accumulation of genomic instability, unresolvable DNA damage, and mitochondrial dysfunction gradually overwhelms intracellular quality-control mechanisms. Concurrently, epigenetic drift and chronic, low-grade systemic inflammation ("inflammaging") dismantle the stem cell niche, driving adult stem cell exhaustion and shifting wound healing away from functional tissue replacement toward maladaptive fibrosis. Furthermore, we examine divergent, organ-specific repair trajectories. By contrasting the severe regenerative restrictions of the adult central nervous system and myocardium with the persistent, yet exhaustible, resilience of the liver, we elucidate the unique intrinsic and microenvironmental barriers that impede structural and functional recovery. Finally, we evaluate the clinical paradigm shift from passive management of age-related degeneration to active restoration of tissue integrity. By integrating systemic geroscience-which addresses the global hallmarks of aging-with targeted bioengineering and in vivo epigenetic modulation, contemporary regenerative medicine seeks to recreate permissive, youthful microenvironments. Ultimately, mastering these ontogenetic principles holds unprecedented potential to reactivate endogenous repair pathways, mitigate multi-organ collapse, and significantly extend human functional healthspan.

DNA repair↗

PubMed1999

Augmentation of ventral tegmental area stimulation-induced feeding by both stimulation and lesion of the contralateral ventral tegmental area in the rat.

Unilateral lesions of the ventral tegmental area (VTA) facilitate behavioral responses (feeding and exploration) induced by electrical stimulation of the VTA in the contralateral hemisphere. It was hypothesized that this facilitation may result from a lesion-induced compensatory increase in dopamine transmission in the intact hemisphere. In the present study we tested on the functional level the hypothesis that the activity of bilateral mesocorticolimbic systems is inversely related. For this purpose we compared the effect of unilateral subthreshold activation with the effect of subsequent unilateral lesion of VTA on feeding response evoked by electrical stimulation of the contralateral VTA. In male Wistar rats implanted with bilateral VTA electrodes stimulation-induced feeding was tested in a latency to feed-stimulation frequency curve-shift paradigm. One electrode was used for induction of feeding reaction and the other electrode was used for concurrent stimulation (with the subthreshold current) and subsequent electrolytic lesioning of the contralateral VTA. It was found that both contralateral stimulation and subsequent lesion performed through the same electrode facilitated a feeding response that manifested as a decrease in the reaction's threshold and a leftward shift of the latency-frequency curve. The paradoxical similarity of the effects of the stimulation and lesion is discussed in terms of functional organization of the mesocorticolimbic system and adaptive changes in dopaminergic transmission.

Animals↗

PubMed1995

Humanism and positivism in nursing: contradictions and conflicts.

Nursing and nurse education have been influenced by a shift towards a broadly humanistic philosophy as a basis for practice. At the same time, in attempts to develop a knowledge base and credibility as a profession, the vital importance of research has been acknowledge. Both these aspects of nursing are increasingly forming the basis for all nursing courses. However, in this paper, it is argued that the implicit adoption of notions of science based in a positivistic paradigm gives rise to conflicts with a humanistic philosophy. It is contended that nursing has inherited a 'legacy of positivism', which promotes objectivity and reductionism and which excludes subjective meaning and the personal from the research process. In part this has been due to the powerful influence of medical hegemony, which has defined the nature of legitimate knowledge and controlled nursing research through the gatekeeping function of doctors. If nursing is to make progress in the development of a knowledge base, the contradictions between humanism and positivism must be acknowledged as a barrier to an integration of the art and science of nursing. This paper suggests that what is required is a paradigm shift, a redefinition of nursing science, which not only rehumanizes the nature of research, but also refutes and challenges the notion of objectivity and the objective attitude.

Conflict, Psychological↗

PubMedDate not supplied

Service management: a New Zealand model for shifting the balance from hospital to community care.

New Zealand's health system has undergone a radical reform in recent years. A central feature of this reform is the area health board, a partly elected and partly appointed body responsible for all health services for its defined population. Within the area health board, the organizational structure which is based upon general management is moving away from institutional towards service or programme management. This is involving clinicians in the management process as service managers, within an accountability structure which cuts across the traditional hospital/community service boundaries. This is a major paradigm shift in health services management which could have major implications for a shift from hospital to community-based care and from secondary to primary health care.

Community Health Services↗

PubMedDate not supplied

Nursing education and healthcare reform.

What and how we teach, how we learn, and how we practice nursing are fundamentally changing. Perspectives on Assessment invites dialogue on assessment's central role in the paradigm shifts currently occurring in nursing education and nursing practice. Programs of assessment in educational and practice institutions offer the opportunity for continuous feedback on the quality and effectiveness of our efforts to prepare nurses who are competent to practice in a healthcare environment that is continuously changing and increasingly community based. The assessment process itself offers the opportunity for us to engage in an ongoing conversation about our progress with these two paradigm changes.

Curriculum↗

PubMedDate not supplied

Assessing competency for community-focused nursing practice.

Clinical Competence↗

PubMedDate not supplied

Learning to 'walk our talk': the implications of sociological theory for research methodologies in health promotion.

In recent formulations of the concept of health promotion, such as Achieving Health for All and the Ottawa Charter, emphasis is clearly placed on comprehensivity and the integration of individual and social determinants of health, broadly defined. This paper is premised on the observation that despite evidence of a paradigm shift in the way we talk about health promotion at a conceptual level, we have yet to properly articulate a 'new' research methodology to accompany the 'new' health promotion. The paper has three main sections. First, some of the limitations and contradictions that separate the rhetoric of health promotion from its current operationalization in research practice are discussed. In asserting the inherent links between theory, methodology and method, the need for a new research paradigm is demonstrated. In the second section, seven key issues derived from the literature on sociological theory are identified and discussed in terms of their implications for choosing a new research methodology for health promotion. In the third section it is suggested that using these issue areas as a 'decision map' leads to the selection of a preferred strategy which brings together both interpretive and critical perspectives to bear on our understanding of social reality as it affects health. Elements of both of these approaches and the nature of their potential complimentarity are considered. Throughout these deliberations the reader is encouraged to consider the potentially conservative or activist orientations that alternate methodologies imply, and to critically evaluate how these mesh with the emerging rhetoric of fostering empowerment that is the cornerstone of the 'new' health promotion.

Health Promotion↗

PubMed2004

Healthy children, healthy country: the use of governing instruments in shifting the policy paradigm.

The evidence on early childhood strongly suggests the need to shift child health policy from the current focus on social welfare to a socio-ecologically based approach. This paper reviews three governing instruments, exhortation, expenditure and regulation, that have been used by governments in Australia and discusses the relative effectiveness of these approaches in shifting the child health policy paradigm.

Editorial↗

PubMed1996

Short-term adaptation of electrically induced saccades in monkey superior colliculus.

1. This study focuses on the neural mechanisms underlying short-term adaptation of saccadic eye movements in the rhesus monkey. Involuntary saccades of various amplitudes and directions (E-saccades) were elicited in complete darkness by electrical stimulation (< or = 50 microA) in the deeper layers of the superior colliculus (SC) at 30 different sites in two monkeys. E-saccades at a given site could be adapted by presenting a visual target at a small distance from the expected end point immediately after their occurrence. The monkeys were trained to null the ensuing error signal by making the appropriate correction saccade to the visual target in many successive trials (E-adap paradigm). By properly adjusting the location of the visual target relative to the end point of the E-saccade, the latter could be modified in amplitude as well as in direction. 2. E-saccade modifications were highly significant, always in the intended direction, and occurred only if a postsaccadic visual error signal was created. These changes were plastic and required a subsequent E-adap series with an opposite error signal to cancel them. Their time course, both during the adaptation and the readaptation period, indicated that the modification was a slow and gradual process, as has been observed earlier in classical visual adaptation experiments. 3. Postadaptation tests, assessing whether the adaptation of E-saccades was also noticeable in normal visually guided saccades (V-saccades), showed incomplete adaptation transfer that was significant in most cases. A similar result, significant in all cases, was obtained with an extended version of the E-adap paradigm in which movement planning on the basis of target selection was possible. In this case, a presaccadic visual target was presented at the expected end point of the E-saccade, which was evoked just before the monkey would make a voluntary saccade itself (VE-adap). 4. In another series of experiments, V-saccades, which were matched to the optimal saccade vector of the particular collicular site under investigation, were adapted with the classical intrasaccadic target shift paradigm (V-adap). In agreement with earlier findings, this V-adaptation showed no transfer to the E-saccades. This result was obtained even in trials in which movement planning on the basis of target selection was possible (VE-test). 5. Our experiments have shown that saccades of collicular origin can be adapted and that presaccadic target selection is not crucial for this process. Both results are nicely in line with an existing model featuring a downstream adaptive corrector with access to SC inputs. This scheme, however, does not explain why the degree of saccadic adaptation, achieved by applying any of the three adaptation paradigms (E-adap, EV-adap, or V-adap), was never equally expressed in V- and E-saccades. Arguments for extending the model by adding a cortical input from the frontal eye fields to the adaptive corrector are discussed.

Adaptation, Physiological↗

PubMed2026

Acute leukemia therapy at a crossroads: from conventional chemotherapy to the era of precision medicine.

Since the discovery of cytotoxic agents in the mid-20th century, acute leukemia has consistently served as a model for oncology research. As the Human Genome Project and subsequent genomic profiling elucidated the landscape of somatic mutations and cytogenetic aberrations driving leukemogenesis, the development of molecularly targeted therapies has dramatically accelerated, yielding significant improvements in patient outcomes. In acute myeloid leukemia (AML), the emergence of selective inhibitors targeting high-frequency alterations such as FLT3, NPM1, and IDH1/2 has redefined the standard of care, demonstrating superior efficacy when combined with conventional intensive chemotherapy or hypomethylating agents. Simultaneously, for acute lymphoblastic leukemia (ALL), in addition to the significant improvements achieved by tyrosine kinase inhibitors (TKIs) for BCR-ABL-positive ALL, the advent of CD19- or CD22-targeted monoclonal antibodies and CAR-T cell therapies has marked an epoch-making milestone, representing a major paradigm shift in the management of relapsed or refractory cases. Bridging these two distinct lineages, menin inhibitors have emerged as a novel class of agents targeting a common pathogenic mechanism in KMT2A-rearranged AML/ALL and NPM1-mutated AML, exhibiting promising antileukemic activity across these subtypes. In this review, we describe the evolution of leukemia therapy-highlighting historical trajectory across AML, APL, and ALL from uniform cytotoxic chemotherapy to molecularly targeted agents, antibody-based therapies, and chemo-free paradigms, while outlining future perspectives for precision hematology.

Acute lymphoblastic leukemia↗

PubMed1996

[Assessment of attention parameters in sleep apnea patients].

In the current study the modality-shift paradigm was applied to examine attention deficits in sleep-apnea patients. The reaction times of ipsi- and crossmodal light and sound stimuli were measured on 34 patients presenting symptoms of sleep-apnea. Some of the simple reaction times of ipsimodal (light-light; sound-sound) and crossmodal (light-sound; sound-light) stimuli correlated with mean or with minimal oxygen saturation, but did not correlate with the frequency or duration of obstructive apneas and hypopneas. However, results are different if the amount of modality-shift effect is taken into consideration. Significant correlations were found for the maximal duration of obstructive apneas and hypopneas as well as for mean oxygen saturation.

Attention↗

PubMed2003

Shifts in diagnostic frequencies during the years 1975-1999.

Data on discharge diagnoses was obtained from a state-supported mental hospital located in the mid-Atlantic region of the United States for the years 1975 through 1999. Results indicated that frequencies of diagnosis of major mental disorders changed significantly during this interval, with reciprocal changes between schizoaffective and affective disorders and schizophrenia. Percentages of total discharge diagnoses of major affective disorders increased threefold, diagnoses of schizoaffective disorders increased fivefold, and schizophrenia diagnoses decreased threefold during the interval of study. Several of these trends were contemporaneous with changes in successive editions of the Diagnostic and Statistical Manual of Mental Disorders. Additional factors that may have contributed to changes in diagnostic rates include increased access to disability payments, changes in third-party payment policies and institutional funding priorities, access to improved medications, paradigm shifts, and changes in actual incidence of the disorders. Consistent with changed social policies, length of stay decreased for all groups during the interval 1975-1999.

Adult↗

PubMed1996

Anabolic-androgenic steroids and brain reward.

Anabolic-androgenic steroid (AAS) effects on brain reward were investigated in male rats with electrodes implanted in the lateral hypothalamus using the rate-frequency curve shift paradigm of brain stimulation reward. In the first experiment, treatment for 2 weeks with the AAS methandrostenolone had no effect on either the reward or performance components of intracranial self-stimulation. In the second experiment, treatment for 15 weeks with an AAS "cocktail" consisting of testosterone cypionate, nandrolone decanoate, and boldenone undecylenate did not alter brain reward but did produce a slight but significant change in bar press rate. In addition to the AAS treatment, animals in the second study were administered a single injection of d-amphetamine before and after 15 weeks of AAS exposure. The rate-frequency curve shift observed in response to a systemic injection of amphetamine was significantly greater in animals after 15 weeks of treatment with the AAS cocktail. Although AAS do not appear to alter the rewarding properties of brain stimulation, AAS may influence the sensitivity of brain reward systems.

Amphetamine↗