Biomedical subjects

John Doyle

Publications and source records attributed to John Doyle.

13 recordsLinked to original sources

PubMed2003

A pharmacoeconomic evaluation of the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study in the United Kingdom.

OBJECTIVE: To determine the short-term healthcare costs associated with intensive lipid lowering with atorvastatin initiated within 24-96 hours of the occurrence of acute coronary syndrome (ACS) in patients in the UK. METHODS: Patient-level clinical outcome data from the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial and standard cost data were used to compare the total expected 16-week cost per patient on atorvastatin 80 mg/day versus placebo. Clinical outcomes assessed included the following: death; cardiac arrest with resuscitation; nonfatal myocardial infarction; worsening angina pectoris with objective evidence of myocardial ischaemia requiring rehospitalisation; surgical or percutaneous coronary revascularisation; nonfatal stroke; hospitalisation for angina without objective evidence of myocardial ischaemia; and new or worsening congestive heart failure requiring rehospitalisation. All relevant direct medical costs from the perspective of the NHS were considered. RESULTS: The total expected cost was pound 784.05 per patient in the placebo cohort and pound 851.59 per patient in the atorvastatin cohort, resulting in an incremental cost of pound 67.54 per patient in the atorvastatin group. The cost per event avoided was pound 1762.04. A third of the cost of atorvastatin treatment was offset within 16 weeks by the cost savings resulting from the reduction in the number of events in the atorvastatin cohort compared with the placebo cohort. CONCLUSION: The clinical benefits of short-term intensive atorvastatin treatment administered after ACS is attainable through a marginal increase in 'upfront' costs.

Anticholesteremic Agents↗

PubMed2003

Custody and caring: innovations in Australian correctional mental health nursing practice.

The challenges of delivering quality nursing care to incarcerated offender populations are diverse, complex and pressing. Correctional nursing in prison health facilities is a highly specialized area of mental health care. Research findings have identified contextual influences on the nature of practice and practice arrangements in the correctional environment. Implications for practice innovation and role development are explored through milieu factors.

Female↗

PubMed2003

Economic analysis of oral and topical therapies for onychomycosis of the toenails and fingernails.

OBJECTIVE: Several antifungal agents are indicated for onychomycosis, a fungal infection of the toenails and fingernails. These agents differ in their dosing regimen, efficacy, adverse events profile, potential for drug interaction, and cost. We conducted a pharmacoeconomic analysis of oral and topical therapies for onychomycosis from the perspective of a hypothetical managed care payer to determine the most cost-effective agent. DESIGN: A decision analytic model was developed to evaluate the pharmacoeconomic profiles of itraconazole-continuous (Sporanox, Janssen Pharmaceutica), itraconazole-pulse (Sporanox, Janssen Pharmaceutica), terbinafine (Lamisil, Novartis Pharmaceuticals), and ciclopirox (Penlac, Dermik Laboratories) in the treatment of fingernail and toenail onychomycosis. METHODOLOGY: We conducted a meta-analysis of the available literature to populate the decision analytic model with clinical point estimates for success, failure, and relapse. A panel of expert dermatologists defined resources consumed during the onychomycosis treatment process. These resources were then assigned values, using publicly available data sources, to reflect the U.S. managed care perspective. These clinical and economic data elements were integrated in the decision analytic model to arrive at the expected cost of treatment for each drug. Additionally, incremental cost-effectiveness was calculated for treatment success and disease-free days achieved by each therapy. Finally, a policy-level analysis of the budgetary impact of using the therapies for onychomycosis in a managed care setting was conducted. RESULTS: The meta-analysis demonstrated terbinafine to be the therapeutic alternative with the highest success rate for both fingernails (96.55 percent) and toenails (81.15 percent). Terbinafine also had the lowest relapse rate (6.42 percent) and the highest number of disease-free days for both fingernails and toenails. Subsequently, in terms of cost-effectiveness, terbinafine dominated all other comparators for fingernails and toenails. CONCLUSIONS: Based on the patient-level analysis, we concluded that terbinafine is the most cost-effective therapy in the treatment of onychomycosis from a managed care perspective. Furthermore, at the policy level, increased utilization of terbinafine among onychomycosis patients is likely to reduce the managed care organizations' per member per month cost.

Adult↗

PubMed2002

Overview of the Alliance for Cellular Signaling.

The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.

B-Lymphocytes↗

PubMed2002

Design degrees of freedom and mechanisms for complexity.

We develop a discrete spectrum of percolation forest fire models characterized by increasing design degrees of freedom (DDOF's). The DDOF's are tuned to optimize the yield of trees after a single spark. In the limit of a single DDOF, the model is tuned to the critical density. Additional DDOF's allow for increasingly refined spatial patterns, associated with the cellular structures seen in highly optimized tolerance (HOT). The spectrum of models provides a clear illustration of the contrast between criticality and HOT, as well as a concrete quantitative example of how a sequence of robustness tradeoffs naturally arises when increasingly complex systems are developed through additional layers of design. Such tradeoffs are familiar in engineering and biology and are a central aspect of the complex systems that can be characterized as HOT.

Journal Article↗

PubMed2002

Robustness as a measure of plausibility in models of biochemical networks.

Theory, experiment, and observation suggest that biochemical networks which are conserved across species are robust to variations in concentrations and kinetic parameters. Here, we exploit this expectation to propose an approach to model building and selection. We represent a model as a mapping from parameter space to behavior space, and utilize bifurcation analysis to study the robustness of each region of steady-state behavior to parameter variations. The hypothesis that potential errors in models will result in parameter sensitivities is tested by analysis of two models of the biochemical oscillator underlying the Xenopus cell cycle. Our analysis successfully identifies known weaknesses in the older model and suggests areas for further investigation in the more recent, more plausible model. It also correctly highlights why the more recent model is more plausible.

Animals↗

PubMed2002

Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss.

Our inability to purify hematopoietic stem cells (HSCs) precludes direct study of many aspects of their behavior in the clinical hematopoietic stem cell transplantation (HSCT) setting. We indirectly assessed stem/progenitor cell behavior in the first year after HSCT by examining changes in neutrophil telomere length, X-inactivation ratios, and cycling of marrow progenitors in 25 fully engrafted allogeneic HSCT recipients. Donors were sampled once and recipients at engraftment and 2 to 6 months and 12 months after HSCT. Telomere length was measured by an in-gel hybridization technique, X-inactivation ratios were measured by the human androgen receptor assay, and cell cycle status was determined by flow cytometric analysis of pyronin Y- and Hoechst 33342-stained CD34(+)CD90(+) and CD34(+)CD90(-) marrow cells. Compared with their donors, recipients' telomeres were shortened at engraftment (-424 base pairs [bp]; P <.0001), 6 months (-495 bp; P =.0001) after HSCT, and 12 months after HSCT (-565 bp; P <.0001). There was no consistent pattern of change in telomere length from 1 to 12 months after HSCT; marked, seemingly random, fluctuations were common. In 11 of 11 informative recipients, donor X-inactivation ratios were faithfully reproduced and maintained. The proportion of CD34(+)CD90(+) progenitors in S/G(2)/M was 4.3% in donors, 15.7% at 2 to 6 months (P <.0001) after HSCT, and 11.5% at 12 months after HSCT (P <.0001, versus donors; P =.04, versus 2-6 months). Cycling of CD34(+) CD90(-) progenitors was largely unchanged. We infer that (1) HSCT-induced accelerated telomere loss is temporary and unlikely to promote graft failure or clonal hematopoietic disorders and (2) the striking fluctuations in telomere length and variation in pattern of telomere loss reflect stochastic determination of HSC fate after HSCT.

Adult↗

PubMed2002

Complexity and robustness.

Highly optimized tolerance (HOT) was recently introduced as a conceptual framework to study fundamental aspects of complexity. HOT is motivated primarily by systems from biology and engineering and emphasizes, (i) highly structured, nongeneric, self-dissimilar internal configurations, and (ii) robust yet fragile external behavior. HOT claims these are the most important features of complexity and not accidents of evolution or artifices of engineering design but are inevitably intertwined and mutually reinforcing. In the spirit of this collection, our paper contrasts HOT with alternative perspectives on complexity, drawing on real-world examples and also model systems, particularly those from self-organized criticality.

Journal Article↗

PubMed2002

Mutation, specialization, and hypersensitivity in highly optimized tolerance.

We introduce a model of evolution in which competing organisms are represented by percolation lattice models. Fitness is based on the number of occupied sites remaining after removing a cluster connected to a randomly selected site. High-fitness individuals arising through mutation and selection must trade off density versus robustness to loss, and are characterized by cellular barrier patterns that prevent large cascading losses to common disturbances. This model shows that Highly Optimized Tolerance (HOT), which links complexity to robustness in designed systems, arises naturally through Darwinian mechanisms. Although the model is a severe abstraction of biology, it produces a surprisingly wide variety of micro- and macroevolutionary features strikingly similar to real biological evolution.

Biological Evolution↗

PubMed2002

PVC tracheal tubes exert forces and pressures seven to ten times higher than silicone or armoured tracheal tubes--an in vitro study.

PURPOSE: Many types of tracheal tubes (TT) including silicone, polyvinylchloride (PVC) and armoured have been used for blind tracheal intubation (TI) via the intubating laryngeal mask airway (ILMA) and may cause trauma to the airway. We examined the maximal in vitro forces and pressures exerted by the tip of various TT as it exits the ILMA. METHODS: Silicone, PVC and armoured TT were studied. A #5 ILMA was secured on a wooden platform. With the use of a Harvard pump, force was applied to push the TT through the ILMA at 0.34 cm*sec(-1). Forces exerted to push the TT and forces exerted by the TT tips on distal objects were calculated using proximal and distal pressure manometres. The areas of contact between the distal TT tips and the distal objects were measured by planimetry of an imprint. The final pressures exerted by the TT tips on a fixed distal object were calculated by dividing the forces exerted by the areas of contact. RESULTS: When compared to silicone and armoured TT, PVC TT exerted seven to ten times higher forces and pressures on distal objects. (P < 0.05). Heating PVC TT and inserting PVC TT with reverse curvature to the ILMA did not decrease the forces and pressures exerted by the distal tip. CONCLUSION: The high forces and pressures exerted by PVC TT may theoretically contribute to increased morbidity to patients' airway and esophagus. Caution should be exercised before attempting blind TI via the ILMA with a PVC TT.

Intubation, Intratracheal↗

PubMed2002

Transfusion-associated graft versus host disease.

OBJECTIVES: To review the epidemiology, pathophysiology, therapeutic and preventive strategies of transfusion associated graft versus host disease (TA-GVHD) and relate the findings to the critically ill child. DESIGN: Review article of published medical literature related to TA-GVHD. DATA SOURCES: Medline, bibliography search, published national and institutional guidelines. STUDY SELECTION: Original publications including prospective studies, case reports, case series, laboratory studies, and animal work. DATA EXTRACTION: Data were extracted manually after we reviewed selected articles and assessed their contribution to knowledge of TA-GVHD. DATA SYNTHESIS: New and significant historic information from the selected publications relating to incidence, therapy, prevention, and complications of preventive therapy of TA-GVHD was incorporated. CONCLUSIONS: Pediatric critical care practitioners should be aware of this preventable but fatal complication of cellular blood product transfusion. High-risk categories include congenital and acquired immunodeficiency, younger age, transfusion of blood donated by family members, and transfusion with fresh whole blood. Children at risk for the development of TA-GVHD include neonates, infants, and children with congenital heart disease, not restricted to children with "classic" DiGeorge syndrome. At present, risk identification and targeted prevention are the only methods to manage TA-GVHD. Aside from minimizing cellular blood product exposure, blood product irradiation is the only established and widely available method to prevent TA-GVHD. Transfusion guidelines need to reflect a balance between the incidence of TA-GVHD and the costs of instituting irradiation to selected groups or as routine transfusion policy.

Journal Article↗

PubMed2002

Best practice treatment algorithm for primary open-angle glaucoma: implications for U.S. ophthalmology practice.

The objective of this study was to develop a "best-practice" treatment algorithm for the management of primary open-angle glaucoma in patients receiving initial medical therapy, to serve as a consideration for future ophthalmology practice. For comparison, a baseline, "common-practice" treatment algorithm was also created that reflects current ophthalmology practice patterns. Survey instruments were developed based on a comprehensive review of relevant literature, along with input from a general ophthalmologist. A panel of eight ophthalmologists subspecialized in glaucoma management was surveyed. Consensus was achieved using a modified Delphi technique. A comparison of common- and best-practice treatment algorithms suggests that in contrast with expert opinion, nonselective beta blockers are currently used more often, and alpha-2 agonists less often, as first-line therapy for the treatment of primary open-angle glaucoma.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Allogeneic bone marrow transplantation in children with chronic myelogenous leukemia.

PURPOSE: To determine the outcome of children undergoing allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML) at the authors' institution. PATIENTS AND METHODS: Between 1985 and 1999, 18 allogeneic bone marrow transplantations were performed in 17 patients with CML at the Hospital for Sick Children in Toronto. Median age at diagnosis was 9.5 years (range 3-17). Fourteen patients had disease in the first chronic phase, one had disease in the second chronic phase, and two had disease in the accelerated phase. Preparative regimens varied, with radiation-based protocols used in eight patients. Thirteen donors were related (11 matched, 2 mismatched); four were unrelated (2 matched, 2 mismatched). Patients received T-cell-replete bone marrow a median of 7.5 months (range 2.2-22) from diagnosis. A median of 3.0 x 10(8)/kg nucleated cells was infused (range 1.6-6.7). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in 13 children. cyclosporine in three, and methotrexate in one. RESULTS: Primary graft failure occurred in one patient. Grade 2 acute GVHD or more developed in 11 of the 17 children (64%; grade 2 in 4, grade 3 in 7). Chronic GVHD occurred in 6 of the 16 patients at risk (37.5%; 5 extensive, 1 localized). No patient experienced overt or cytogenetic relapse. There were two deaths (12%): one from acute GVHD and cytomegalovirus pneumonia and the other from chronic GVHD. Probability of 5-year event-free survival was 87 +/- 9%. CONCLUSIONS: These results strongly support the practice of allotransplantation in children with CML, even in the setting of advanced disease and histoincompatibility. Efforts should be aimed at reducing the transplantation-related death rate.

Adolescent↗