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Biomedical subjects

Andrew Knight

Publications and source records attributed to Andrew Knight.

17 recordsLinked to original sources
PubMed2006

Observations of residents' work activities for 24 consecutive hours: implications for workflow redesign.

PURPOSE: To examine resident workflow as part of an institutional approach to redesigning the processes of health care delivery. METHOD: In 2003 the authors observed the workflows for 24 hours of seven residents who were at various levels of training (two each from the internal medicine, pediatrics, and obstetrics and gynecology programs, and one from general surgery) at Denver Health Medical Center, an urban, public teaching hospital. RESULTS: Although the residents spent varying proportions of their time in various activities, all had extremely fragmented workflows as they engaged in from 5.0 to 11.3 different activities per hour of nonsleeping time, many of which required only minutes to complete. All residents experienced frequent interruptions and changes in focus. The internal medicine and surgery residents spent large amounts of time traveling, covering three and six miles, respectively, during their 24-hour shifts. Three of the residents slept between one-quarter and one-third of their time on duty (one without any interruption). CONCLUSIONS: The authors suggest that fragmented workflow exists in all residency programs and that applying the same work limitations to all residents in all training programs (to reduce fatigue-related errors) may be overly restrictive. Improving these processes of care will be difficult and will likely require analytic skills and knowledge of systems engineering that most physicians do not have.

Delivery of Health Care↗
PubMed2006

Animal carcinogenicity studies: 1. Poor human predictivity.

The regulation of human exposure to potentially carcinogenic chemicals constitutes society's most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation's International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors.

Animals↗
PubMed2006

Animal carcinogenicity studies: 2. Obstacles to extrapolation of data to humans.

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were effects on a particularly wide variety of organ systems. The likely causes of the poor human predictivity of rodent carcinogenicity bioassays include: 1) the profound discordance of bioassay results between rodent species, strains and genders, and further, between rodents and human beings; 2) the variable, yet substantial, stresses caused by handling and restraint, and the stressful routes of administration common to carcinogenicity bioassays, and their effects on hormonal regulation, immune status and predisposition to carcinogenesis; 3) differences in rates of absorption and transport mechanisms between test routes of administration and other important human routes of exposure; 4) the considerable variability of organ systems in response to carcinogenic insults, both between and within species; and 5) the predisposition of chronic high dose bioassays toward false positive results, due to the overwhelming of physiological defences, and the unnatural elevation of cell division rates during ad libitum feeding studies. Such factors render profoundly difficult any attempts to accurately extrapolate human carcinogenic hazards from animal data.

Animals↗
PubMed2006

Animal carcinogenicity studies: 3. Alternatives to the bioassay.

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly difficult any attempts to accurately extrapolate animal data in order to predict carcinogenic hazards to humans. Proposed modifications to the conventional bioassays have included the elimination of mice as a second species, and the use of genetically-altered or neonatal mice, decreased study durations, initiation-promotion models, the greater incorporation of toxicokinetic and toxicodynamic assessments, structure-activity relationship (computerised) systems, in vitro assays, cDNA microarrays for detecting changes in gene expression, limited human clinical trials, and epidemiological research. The potential advantages of non-animal assays when compared to bioassays include the superior human specificity of the results, substantially reduced time-frames, and greatly reduced demands on financial, personnel and animal resources. Inexplicably, however, the regulatory agencies have been frustratingly slow to adopt alternative protocols. In order to decrease the enormous cost of cancer to society, a substantial redirection of resources away from excessively slow and resource-intensive rodent bioassays, into the further development and implementation of non-animal assays, is both strongly justified and urgently required.

Animal Testing Alternatives↗
PubMed2006

Animal carcinogenicity studies: implications for the REACH system.

The 2001 European Commission proposal for the Registration, Evaluation and Authorisation of Chemicals (REACH) aims to improve public and environmental health by assessing the toxicity of, and restricting exposure to, potentially toxic chemicals. The greatest benefits are expected to accrue from decreased cancer incidences. Hence the accurate identification of chemical carcinogens must be a top priority for the REACH system. Due to a paucity of human clinical data, the identification of potential human carcinogens has conventionally relied on animal tests. However, our survey of the US Environmental Protection Agency's (EPAs) toxic chemicals database revealed that, for a majority of the chemicals of greatest public health concern (93/160, i.e. 58.1%), the EPA found animal carcinogenicity data to be inadequate to support classifications of probable human carcinogen or non-carcinogen. A wide variety of species were used, with rodents predominating; a wide variety of routes of administration were used; and a particularly wide variety of organ systems were affected. These factors raise serious biological obstacles that render accurate extrapolation to humans profoundly difficult. Furthermore, significantly different International Agency for Research on Cancer assessments of identical chemicals, indicate that the true human predictivity of animal carcinogenicity data is even poorer than is indicated by the EPA figures alone. Consequently, we propose the replacement of animal carcinogenicity bioassays with a tiered combination of non-animal assays, which can be expected to yield a weight-of-evidence characterisation of carcinogenic risk with superior human predictivity. Additional advantages include substantial savings of financial, human and animal resources, and potentially greater insights into mechanisms of carcinogenicity.

Animals↗
PubMed2005

Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity.

Cisplatin causes apoptosis of dorsal root ganglia (DRG) neurons. The amount of platinum binding to DNA correlates with cisplatin toxicity in cancer cellsGenomic DNA platinum content of cultured embryonic DRG neurons and PC12 cells was assayed using inductively coupled plasma mass spectrometry (ICP-MS). Throughout these studies, "cisplatin" refers to the specific drug; "platinum" to the bound form of the drug that is measured in ICP-MS.. Cisplatin binds neuronal DNA more than a neuron-like dividing cell line (PC12); 10-fold at 24 h and 24-fold greater at 72 h. Difference in platinum accumulation was not due to dividing versus post-mitotic state, or to a difference in rate of repair. There was overall greater accumulation of platinum in DRG neurons. In vivo DNA-Platinum binding in adult (300 g) rat DRG was greater than in multiple other tissues. Concomitant treatment with high-dose NGF prevented cisplatin-mediated neuronal apoptosis in vitro but did not reduce adduct formation. Our results show that NGF does not alter platination of DNA, indicating that it interrupts the platinum death pathway after adduct formation. In addition, disproportionate platinum accumulation may explain why a drug aimed at killing rapidly dividing cells causes sensory neurotoxicity.

Animals↗
PubMed2005

"Concepts in animal welfare": a syllabus in animal welfare science and ethics for veterinary schools.

Public attitudes toward animal welfare have improved with growing social affluence, and veterinarians are increasingly expected to be informed about animal welfare in a broader sense than health alone. However, animal welfare has not been a traditional component of the veterinary curriculum. To help address this lack, the World Society for the Protection of Animals(WSPA) and the University of Bristol School of Veterinary Science launched the ''Concepts in Animal Welfare'' syllabus in 2003. This comprehensive syllabus comprises seven core and 23 elective modules and covers a range of animal welfare issues, including farm and companion animal welfare, wildlife, and the use of animals in experiments. There are also modules on ethics and animal legislation. The syllabus is interactive, promotes critical analysis of issues from different angles, and may be adapted for use in any veterinary curriculum. WSPA provides training and workshops in developing countries and assists with the implementation of the syllabus.

Animal Welfare↗
PubMed2005

External clinical teaching visits in the regionalised environment.

BACKGROUND: The external clinical teaching (ECT) visit remains integral to the programs of all regional providers of the Australian General Practice Training (AGPT) program. METHOD: All 22 regional training providers (RTPs) were contacted by mail and telephone regarding their use of ECT visits. RESULTS: Responses were received from 17 of the 22 RTPs. There was considerable variation in approach to visitor training, reporting formats, provision of manuals, and the stated purpose of the visits. DISCUSSION: This study has provided a clearer picture of how ECT visits are functioning in the regionalised environment. There remains considerable variation in the use of these visits in Australian general practice training. New national guidelines promoting educational quality in ECT visits and protecting the diversity of regionalisation should be implemented. The use of these visits for performance appraisal needs further discussion.

Australia↗
PubMed2005

Three years of registrar rural exemptions--a review of a novel approach.

BACKGROUND: The Australian General Practice Training Program (AGPT) requires all registrars to undertake at least 6 months of training in rural areas. This can cause significant stress for general pathway registrars. Central to a fair, safe process for application of this policy is an equitable and humane rural exemption process. OBJECTIVE: WentWest's independent exemption assessment committee, consisting of an urban medical educator from another provider, a rural registrar liaison officer from another provider, and a lawyer, is described. OUTCOMES: The committee provides an independent, transparent and equitable process which protects the mentoring relationship between educators and registrars. Strict application of the AGPT criteria sometimes lacks compassion, suggesting the need for review of the criteria and some changes to committee function. DISCUSSION: The independent external committee may provide a model for decision making in other contentious areas of general practice training, such as remediation. The mandatory rural training policy requires reassessment 4 years after regionalisation, regarding its impact on workforce, learning and registrar wellbeing.

Australia↗
PubMed2005

Systems change in Australian general practice--early impact of the National Primary Care Collaboratives.

BACKGROUND: The capacity to translate research findings into clinical practice is a core skill for general practice registrars if we are to bridge the gap between evidence and practice, thus improving quality of care. OBJECTIVE: The National Primary Care Collaboratives approach is described as a way of improving health outcomes through systems change, more closely linking local practice with structures which have been proved to be effective elsewhere. The opportunity for general practice registrars to learn from and be involved in this approach is discussed. DISCUSSION: Competencies in systems based approaches and practice based learning are part of modern practice and should be embedded within the revised Royal Australian College of General Practitioners (the RACGP) curriculum. The National Primary Care Collaboratives Program is well placed to assist in the acquisition of these competencies.

Australia↗
PubMed2004

The collaborative method. A strategy for improving Australian general practice.

BACKGROUND: The United Kingdom National Primary Care Collaborative (NPCC) is said to be the largest health service improvement project in the world. The 2000 practices participating serve 11.5 million patients throughout the UK. Improvements such as a 60% reduction in waiting times to see a general practitioner and a four-fold reduction in coronary heart disease mortality have drawn the attention of policy makers in Australia. In 2003, I accompanied a group of Australians to Manchester in the UK to participate in an international training course in collaboratives hosted by the NPCC. The Australian government has recently called for tenders to run the Australian Primary Care Collaborative (APCC) program. OBJECTIVE: To describe the NPCC and discuss how the methodology could be adapted and applied to Australia. DISCUSSION: The Australian primary health care system faces challenges in application of evidence to patient care. Collaborative methodology warrants consideration to address these. Differences including distance, business issues, remuneration mechanisms, infrastructure deficiencies and clinician cynicism present challenges in adaptation and application to Australia. Given adequate support, an APCC could empower general practices to continue to make improvements in many areas of activity.

Australia↗
PubMed2003

A multi-domain protein system based on the HC fragment of tetanus toxin for targeting DNA to neuronal cells.

One goal of gene therapy is the targeted delivery of therapeutic genes to defined tissues. One attractive target is the central nervous system as there are several neuronal degenerative diseases which may be amenable to gene therapy. At present there is a lack of delivery systems that are able to target genes specifically to neuronal cells. Multi-domain proteins were designed and constructed to facilitate the delivery of exogenous genes to neuronal cells. Neuronal targeting activity of the proteins was achieved by inclusion of the HC fragment of tetanus toxin (TeNT), a protein with well-characterised tropism for the central nervous system. The yeast Gal4 DNA-binding domain enabled specific binding of DNA while the translocation domain from diphtheria toxin (DT) was included to facilitate crossing of the endosomal vesicle. One multi-domain protein, containing all three of these domains, was found to transfect up to 8% of neuroblastoma N18-RE105 cells with marker genes. Monitoring the transfection by confocal microscopy indicated that this protein-DNA transfection complex is to some extent localised at the cell surface, suggesting that further improvements to translocating this membrane barrier may yield higher transfection levels. The demonstration that this multi-domain protein can target genes specifically to neuronal cells is a first step in the development of novel vectors for the delivery of genes with therapeutic potential to diseased neuronal tissues.

Animals↗
PubMed2003

Physiological responses to indoor rock-climbing and their relationship to maximal cycle ergometry.

PURPOSE: To quantify the cardiorespiratory responses to indoor climbing during two increasingly difficult climbs and relate them to whole-body dynamic exercise. It was hypothesized that as climbing difficulty increased, oxygen consumption ([V02] and heart rate would increase, and that climbing would require utilization of a significant fraction of maximal cycling values. METHODS: Elite competitive sport rock climbers (6 male, 3 female) completed two data collection sessions. The first session was completed at an indoor climbing facility, and the second session was an incremental cycle test to exhaustion. During indoor climbing subjects were randomly assigned to climb two routes designated as "harder" or "easier" based on their previous best climb. Subjects wore a portable metabolic system, which allowed measurement of oxygen consumption [V02], minute ventilation ([V02]E), respiratory exchange ratio (RER), and heart rate. During the second session, maximal values for [V02], [V02]E, RER, and heart rate were determined during an incremental cycle test to exhaustion. RESULTS: Heart rate and [VO2], expressed as percent of cycling maximum, were significantly higher during harder climbing compared with easier climbing. During harder climbing, %HR(max) was significantly higher than %[V02] (2max) (89.6% vs 51.2%), and during easier climbing, %HR(max) was significantly higher than %[V02] (2max) (66.9% vs 45.3%). CONCLUSIONS: With increasing levels of climbing difficulty, there is a rise in both heart rate and [V02]. However, there is a disproportional rise in heart rate compared with [V02], which we attribute to the fact that climbing requires the use of intermittent isometric contractions of the arm musculature and the reliance of both anaerobic and aerobic metabolism.

Adolescent↗