PubMed Health⌕ Search

Biomedical subjects

John Fox

Publications and source records attributed to John Fox.

At least 19 recordsLinked to original sources
PubMed2026

Real-World Actionability Analysis of Comprehensive Genomic Profiling Versus Single/Small-Gene Panels.

INTRODUCTION: Comprehensive genomic profiling (CGP) enables identification of patients eligible for targeted treatments, making it essential in the management of advanced cancer. This retrospective real-world study compared actionable mutations in CGP-tested patients with advanced/metastatic solid tumors to those who received single-gene/small-panel (SP) tests. METHODS: Patients aged > 18 years with advanced/metastatic solid tumors (including non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, breast cancer, or melanoma) with a CGP or SP test reported between 1 January 2018, and 31 December 2022, were included. OncoKB-derived actionability was compared between the two cohorts. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline characteristics. A weighted generalized linear model with log link was used to report actionability ratio (AR) and 95% confidence intervals (CI). RESULTS: Among 406 patients (CGP-tested cohort: 202, SP-tested cohort: 204), approximately half were diagnosed with NSCLC. After adjusting for baseline characteristics, CGP testing detected more actionable alterations than SP: OncoKB level 1 (50.0% versus 31.4%; AR 1.76 [95% CI: 1.24, 2.51]; p = 0.002), OncoKB level 2 (22.8% versus 10.3%; AR 2.53 [95% CI: 1.17, 5.48]; p = 0.018), and OncoKB level 1 or level 2 or level R1 (55.9% versus 41.2%; AR 1.5 [95% CI: 1.11, 2.01]; p = 0.008). CONCLUSIONS: CGP testing identified more actionable genetic alterations compared with SP testing methods for patients with advanced/metastatic NSCLC, colorectal cancer, prostate cancer, breast cancer, or melanoma. Expanding reimbursement and coverage for CGP testing as well as expanding CGP use can facilitate equitable treatment access for patients with advanced/metastatic cancer.

Actionable mutations↗
PubMed2007

Treatment of skeletally mature ovariectomized rhesus monkeys with PTH(1-84) for 16 months increases bone formation and density and improves trabecular architecture and biomechanical properties at the lumbar spine.

UNLABELLED: Histomorphometric studies of treatments for osteoporosis in humans are restricted to iliac crest biopsies. We studied the effects of PTH(1-84) treatment at the lumbar spine of skeletally mature ovariectomized rhesus monkeys. PTH increased bone turnover, rapidly normalized BMD, and increased vertebral compressive strength. PTH increased trabecular bone volume primarily by increasing trabecular number by markedly increasing intratrabecular tunneling. INTRODUCTION: Histomorphometric studies of the anabolic properties of PTH(1-84) (PTH) and related peptides in human bone are restricted to iliac crest biopsies. The ovariectomized (OVX) monkey is an accepted model of human postmenopausal bone loss and was used to study the effects of PTH treatment at clinically relevant skeletal sites. MATERIALS AND METHODS: Skeletally mature rhesus monkeys were OVX or sham-operated and, after a bone depletion period of 9 months, treated daily for 16 months with PTH (5, 10, or 25 microg/kg). Markers of bone formation (serum osteocalcin) and resorption (urine N-telopeptide [NTX]) and lumbar spine BMD were measured throughout the study. Trabecular architecture and vertebral biomechanical properties were quantified at 16 months. RESULTS: PTH treatment induced dose-dependent increases in bone turnover but did not increase serum calcium. Osteocalcin was significantly increased above OVX controls by 1 month. NTX was significantly elevated at 1 month with the highest dose, but not until 12 months with the 5 and 10 microg/kg doses. Lumbar spine BMD was 5% lower in OVX than in sham animals when treatment was started. All PTH doses increased BMD rapidly, with sham levels restored by 3-7 months with 10 and 25 microg/kg and by 16 months with 5 microg/kg. PTH treatment increased trabecular bone volume (BV/TV), primarily by increasing trabecular number, and dose-dependently increased bone formation rate (BFR) solely by increasing mineralizing surface. The largest effects on BV/TV and yield load occurred with the 10 microg/kg dose. The highest dose reduced trabecular thickness by markedly increasing intratrabecular tunneling. CONCLUSIONS: PTH treatment of OVX rhesus monkeys increased bone turnover and increased BV/TV, BMD, and strength at the lumbar spine. All PTH doses were safe, but the 10 microg/kg dose was generally optimal, possibly because the highest dose resulted in too marked a stimulation of bone remodeling.

Animals↗
PubMed2006

Interaction dynamics of neuronal oscillations analysed using wavelet transforms.

This paper describes the use of a computational tool based on the Morlet wavelet transform to investigate the interaction dynamics between oscillations generated by two anatomically distinct neuronal populations. The tool uses cross wavelet transform, coherence, bi-spectrum/bi-coherence and phase synchronization. Using specimen data recorded from the hippocampus of a rat with experimentally induced focal epilepsy, linear and non-linear correlations between neuronal oscillations in the CA1 and CA3 regions have been computed. The results of this real case study show that the computational tool can successfully analyse and quantify the temporal interactions between neuronal oscillators and could be employed to investigate the mechanisms underlying epilepsy.

Animals↗
PubMed2006

Quantification of recombinant human parathyroid hormone (rhPTH(1-84)) in human plasma by immunoassay: commercial kit evaluation and validation to support pharmacokinetic studies.

Immunoassays utilizing commercial kits designed for diagnostic use can be adapted and validated to meet Good Laboratory Practice (GLP) requirements to support pharmacokinetic (PK) studies. We illustrate in this paper a systematic approach for commercial kit evaluation and GLP-compliant method validation to establish selectivity, sensitivity, linearity, accuracy, precision and stability. Immunoassay kits for human parathyroid hormone (hPTH) quantification from three different vendors were assessed in a side-by-side comparison for their suitability for the PK analysis of recombinant humanPTH (rhPTH) in EDTA plasma. Two immunoradiometric (IRMA) assay kits and one immunoluminometric assay (ILMA) kit were evaluated. Since PTH is present as an endogenous component of human plasma, QC preparation in the biological matrix was handled differently than for a xenobiotic drug compound. The endogenous concentration of PTH was determined in plasma samples from 32 individual lots using the three kits. The lots with the lowest endogenous concentrations of PTH were selected, pooled to form the low QC and spiked with rhPTH to prepare the mid and high QCs. Four evaluation batches were run with each of the three commercial kits to evaluate reference standard linearity, and QC accuracy and precision. Selectivity against PTH peptide fragments PTH(7-84) and PTH(3-84) were assessed by cross-reactivity and accurate spike-recovery to the QC samples at two concentrations. One of the kits was chosen for full method validation because it had the lowest cross-reactivity against hPTH fragments (3-84) and (7-84), a wider dynamic range and the least total error. The accuracy and precision from six validation batches of the QCs were <or=8.1% C.V. and <or=7.9% R.E., respectively. Method robustness was shown by acceptable QC performance using a different batch of capture antibodies, through 12 batches of iodinated detection antibodies, and by the use of four analysts over 2 years of patient sample analysis from clinical trials.

Drug Stability↗
PubMed2006

Automatic generation of spoken dialogue from medical plans and ontologies.

This paper presents some research undertaken as part of the EU-funded HOMEY project, into the application of intelligent dialogue systems to healthcare systems. The work presented here concentrates on the ways in which knowledge of underlying task structure (e.g., a medical guideline) can be combined with ontological knowledge (e.g., medical semantic dictionaries) to provide a basis for the automatic generation of flexible and re-configurable dialogue. This approach is next evaluated via a specific application that provides decision support to general practitioners to help determine whether or not a patient should be referred to a cancer specialist. The competence of the resulting dialogue application, its speech recognition performance, and dialogue performance are all evaluated to determine the applicability of this approach.

Artificial Intelligence↗
PubMed2006

Capturing expert knowledge with argumentation: a case study in bioinformatics.

MOTIVATION: The output of a bioinformatic tool such as BLAST must usually be interpreted by an expert before reliable conclusions can be drawn. This may be based upon the expert's experience, additional data and statistical analysis. Often the process is laborious, goes unrecorded and may be biased. Argumentation is an established technique for reasoning about situations where absolute truth or precise probability is impossible to determine. RESULTS: We demonstrate the application of argumentation to 3D-PSSM, a protein structure prediction tool. The expert's interpretation of results is represented as an argumentation framework. Given a 3D-PSSM result, an automated procedure constructs arguments for and against the conclusion that the result is a good predictor of protein structure. In addition to capturing the unique expertise of the author of 3D-PSSM for distribution to users, an improvement in recall of 5-10 percentage points is achieved. This technique can be applied to a wide range of bioinformatic tools. AVAILABILITY: Example public server and benchmarking data are available at http://www.sbg.bio.ic.ac.uk/~brj03/argumentation/paper/. Source code available on request.

Amino Acid Sequence↗
PubMed2006

Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats.

The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid-and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 microg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 microg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.

Animals↗
PubMed2006

"Notice how you feel": an alternative to detached concern among hospice volunteers.

Medical schools teach physicians to practice "detached concern," a simultaneous emotional distance from and sensitivity toward their patients. Medical students learn detachment to protect themselves from emotion-laden experiences, including death and dying, by employing mechanisms of defense and adjustment, such as suppression and repression of emotions. In this study, the author inquires whether hospice volunteers are trained for and practice detached concern and finds that hospice volunteers are trained for concern. They are concerned for the well-being of patients and their families. The author argues that concern is a social product that can be trained; hospice volunteers are not trained to suppress and repress their emotions, and the hospice as an institution produces and transmits cultural norms, values, and practices surrounding death and dying, thus maintaining a pool of concerned volunteers.

Adaptation, Psychological↗
PubMed2006

Decision support for health care: the PROforma evidence base.

Cancer Research UK has developed PROforma, a formal language for modelling clinical processes, along with associated tools for creating decision support, care planning, clinical workflow management and other applications. The PROforma method has been evaluated in a variety of settings: in primary health care (prescribing, referral of suspected cancer patients, genetic risk assessment) and in specialist care of patients with breast cancer, leukaemia, HIV infection and other conditions. About nine years of experience have been gained with PROforma technologies. Seven trials of decision support applications have been published or are in preparation. Each of these has shown significant positive effects on a variety of measures of quality and/or outcomes of care. This paper reviews the evidence base for the clinical effectiveness of these PROforma applications, and previews the CREDO project -- a multi-centre trial of a complex PROforma application for supporting integrated breast cancer care across primary and secondary care settings.

Breast Neoplasms↗
PubMed2005

An ontological approach to modelling tasks and goals.

Current approaches to modelling plans and processes in AI are limited by current understanding of "goals" and "intentions". We discuss this question in a medical context, viewing goals as clinical objectives and plans and processes as collections of tasks to achieve those objectives. The specific context for this discussion is the CREDO project, which aims to develop a comprehensive approach to supporting complex treatment plans and care pathways and provides an opportunity to carry out an extensive investigation of the key problem of formalising goals in medical informatics and AI generally. A review of 222 clinical services required in the management of breast cancer has yielded a systematic classification of tasks involved in breast cancer care and a similar classification of the clinical goals associated with these tasks. A six-component model of goal structure is proposed based on these ontological analyses. Although the model has been derived from a corpus of examples from medicine many of the issues encountered, and the solution proposed, appear to be relevant to other domains.

Artificial Intelligence↗
PubMed2005

Female adolescents with anorexia nervosa and their parents: a case-control study of exercise attitudes and behaviours.

BACKGROUND: Few studies of physical activity in patients with anorexia nervosa (AN) have included a suitable control group. Nor has such research considered the influence of parents' activity on that of their children. Our first prediction was that adolescents with AN would be significantly more active than healthy controls both prior to, and during, the progression of their disorder. We also expected that the activity levels of parents and their daughters would be correlated, and that this relationship would be stronger in patient than control families. Finally, we expected that the AN parents would be more active and report a greater commitment to exercise than the control parents. METHOD: In a case-control design, we employed multiple indicators of physical activity from adolescent females and their parents, using longitudinal, retrospective, self-report measurements. RESULTS: AN patients were significantly more active than controls both during the course of their disorder and prior to its onset. Parents' activity related to their daughter's activity, but this relationship was not stronger in the parents of the patients. CONCLUSIONS: Future research is needed to determine whether the relationship between parents' and children's activity levels reflects environmental or genetic influences, or a combination of both factors. The important observation of a significant increase in patients' activity levels at least a year prior to diagnosis of the disorder suggests that enhanced physical activity may play a role in the development of the disorder. This may also serve as an early warning sign of a subclinical eating disorder in adolescent girls.

Activities of Daily Living↗
PubMed2005

LISA: a web-based decision-support system for trial management of childhood acute lymphoblastic leukaemia.

Continuation chemotherapy is a key component of the treatment of childhood acute lymphoblastic leukaemia. During this treatment phase, weekly dose adjustments are carried out based on current and historical full blood counts (FBCs). The dose decision pathway is complex and suboptimal therapy may result if information on FBC results is not readily available and/or the prescriber is inexperienced. A web-based decision-support system (Leukaemia Intervention Scheduling and Advice, 'LISA') was designed to facilitate access to FBC information across geographical locations and to assist with dosage adjustments. A balanced-block crossover analysis was performed to evaluate the system. Thirty-six clinicians with varying degrees of experience were each asked to decide on appropriate oral chemotherapy dosages for eight simulated cases: four using LISA and four without. LISA significantly reduced the number of erroneous prescriptions (zero of 144 with LISA vs. 54 of 144 without; P < 0.0001) without affecting the number of times subjects deliberately overrode the protocol (seven of 144 times using LISA and six of 144 without). Using LISA reduced the time taken by novices to reach a decision for each case but increased the time taken by experts. Thirty-five of 36 subjects said they would be likely to use the system if it were available. A system like LISA is likely to be acceptable to clinicians, and has the potential to increase protocol compliance and decrease prescribing errors while allowing clinicians to override the protocol in specific cases where sound reasons exist for doing so.

Antineoplastic Agents↗
PubMed2005

The impact of intraoperative echocardiography on clinical outcomes following adult cardiac surgery.

Over the past 30 years, intraoperative echocardiography has become an invaluable diagnostic tool and monitor of cardiac performance for the management of cardiac surgical patients. The essential information provided by intraoperative echocardiography regarding hemodynamic management, cardiac valve function, congenital heart lesions, and great vessel pathology has contributed to its widespread popularity. Numerous investigations have been conducted in an attempt to specifically demonstrate a beneficial impact of intraoperative echocardiography in cardiac surgery. However, there is a relative paucity of data derived from prospective trials in which the use of intraoperative echocardiography has been randomized among various cardiac surgical patient populations to formally ascertain, rather than simply infer, its putative impact on perioperative decision-making and clinical outcomes. Ironically, the popularity of intraoperative echocardiography has imposed ethical limitations on performing randomized trials in patient populations for whom significant benefit has been previously inferred. Nonetheless, significant evidence has been published to support its almost universal acceptance as an important perioperative diagnostic tool and monitor for cardiac surgical patients. This review focuses on the impact of intraoperative echocardiography on clinical outcomes in the more common adult cardiac surgical scenarios, including coronary artery bypass graft surgery, mitral and aortic valve surgery, and in evaluating the intrathoracic aorta.

Aorta, Thoracic↗
PubMed2004

Muscle pyruvate availability can limit the flux, but not activation, of the pyruvate dehydrogenase complex during submaximal exercise in humans.

While lowering muscle glycogen availability to an extent that would reduce muscle pyruvate formation during intense exercise, we investigated the importance of muscle pyruvate availability to pyruvate dehydrogenase complex (PDC) activation during intense exercise in human skeletal muscle. The present study demonstrated that regardless of whether pre-exercise muscle glycogen content was at a habitual resting concentration (412 +/- 30 mmol (kg dry muscle)(-1)) or depleted (60 +/- 3 mmol (kg dry muscle)(-1)), the increase in PDC activation from its resting value (5.46 +/- 0.96 and 3.67 +/- 0.34 nmol acetyl-CoA min(-1) (mg protein)(-1), respectively) during 10 min of exercise at 75% of the maximum rate of oxygen consumption (VO2max) (delta12.82 +/- 1.72 and delta13.24 +/- 1.42 nmol acetyl-CoA min(-1) (mg protein)(-1), respectively) was the same, despite pyruvate accumulation during exercise being 3-fold lower in the glycogen depleted state (delta0.34 +/- 0.04 and delta0.11 +/- 0.06 mmol (kg dry muscle)(-1), P < 0.001). However, as a result of the reduction in pyruvate availability, calculated flux through the PDC reaction was at least 2-fold lower in the glycogen depleted state compared with normal (21.81 +/- 2.62 and 9.41 +/- 0.63 nmol acetyl-CoA min(-1) (mg protein)(-1), respectively; P < 0.001). It is therefore pertinent to conclude that whilst muscle pyruvate availability appears to be important to the rate of flux through the PDC reaction during in vivo contraction, it is not of primary importance to the control of PDC activation under these conditions, which is probably principally regulated by muscle calcium availability. The proposed central role of pyruvate in muscle PDC activation during in vivo contraction may therefore have been over stated.

Adult↗
PubMed2004

Looking good-family focus on appearance and the risk for eating disorders.

OBJECTIVE: Evidence suggests that eating-disordered families are overly concerned with social appearance and physical attractiveness. However, some argue that parental values are not sufficient to produce disordered eating in their offspring unless combined with certain third-factor effects of the child such as a psychological or biologic vulnerability. We tested this hypothesis by predicting that proneness to anxiety (neuroticism) and a family appearance focus would relate interactively (after controlling for body size) to a measure of weight preoccupation. METHOD: Data from 158 healthy young women were used in the analyses. RESULTS: Statistical analyses confirmed our hypothesis in a multiple regression model that accounted for 42% of the variance in weight preoccupation. DISCUSSION: Findings support the view that family risk factors have a more potent influence on young women who are easily made anxious-perhaps because they are more sensitive to, or more likely to internalize, pressures and expectations to conform to family values.

Adolescent↗