The Total Health Care Audit System: a systematic methodology for clinical practice evaluation and development in NHS provider organizations

Writing in Medical Education in 1982, Fowkes (1982) noted the lack of general agreement within the medical profession on methods of audit, a deficiency previously articulated by Shaw (1980) and later emphasized by McIntyre (1985). More recently, a study by Black & Thompson (1993) of consultant and junior medical staff in four London district general hospitals revealed that 'many doctors did not understand how to undertake audit', and major research by both Hopkins (1993, 1994) and Buttery et al. (1994) described a multiplicity of methodological deficiencies in the general approaches to audit adopted by clinicians since the promulgation of the White Paper definition in 1989. Soundness of methodological approach is fundamental to securing the success of clinical audit within Provider organizations and is thus central to the generation of measurable improvements in the quality of clinical care being delivered to patients. It is therefore disturbing that methodological deficiencies may still be observed in general approaches to audit (Buttery et al. 1994), with no author yet recommending a formal system for critical inquiry into clinical practice. It was the recognition of the unsatisfactory nature of this situation which led us to develop a system aimed at assessing, in a critical fashion, the quality of the totality of care dispensed within NHS provider organizations. The system is presented here for the first time.     

Plasma coenzyme Q(10) in children and adolescents undergoing doxorubicin therapy

The objective of this study was to test the hypothesis that doxorubicin treatment for cancer in childhood and adolescence causes a dose-related decrease in the concentration of plasma coenzyme Q(10). The concentration of plasma coenzyme Q(10) was measured before and after administration of doxorubicin in six patients, and before and after chemotherapy in six patients undergoing treatments that did not include doxorubicin. There was a significant increase in the concentration of plasma coenzyme Q(10) in post-treatment samples compared to pre-treatment samples in patients treated with doxorubicin (P=0.008; n=32), whereas there were no significant changes in plasma coenzyme Q(10) concentrations in patients treated with chemotherapy that did not include doxorubicin. (P=0.770; n=30). We hypothesise that the increase in plasma coenzyme Q(10) that was observed in patients undergoing doxorubicin treatment is due to release of coenzyme Q(10) from apoptotic or necrotic cardiac tissue. We conclude that the cardiotoxicity due to doxorubicin therapy does not involve acute myocardial depletion of coenzyme Q(10).     

Developing nursing care guidelines for children with Hodgkin''s disease

Oncology patients are generally treated on therapeutic research protocols that detail medical treatment. Nursing care is not clearly defined in these protocols; therefore, the need to develop a set of guidelines specifically for nursing care was identified. To further enhance the specialized care that our pediatric oncology patients receive, we developed nursing care guidelines to accompany specific protocols. One of our most highly accruing protocols is designed to treat patients diagnosed with Hodgkin's disease. In an effort to increase understanding of this clinical trial, decrease potential for errors, and improve overall quality of patient care, nursing care guidelines were created. To develop the nursing care guidelines, nurses created a seven-step process: (1) studied the therapeutic protocol, established ongoing interactions with the principal investigator (brainstorming), reviewed benchmarking, (2) created the first draft of the guidelines, compared the formatting of this particular set of guidelines with those previously developed at this setting (drafting), (3) field tested guidelines, (4) revised the guidelines and subjected them to additional field testing, (5) examined the guidelines for implications related to teaching tools, (6) implemented the guidelines through in-services, and (7) developed an evaluation plan with pre- and post-tests that indicated improved disease and treatment knowledge among participating nurses. Potential contributions from implementing nursing care guidelines that parallel therapeutic protocols include more accurate and complete research data collection and a more defined role for nurses in the protocol development process. The guidelines also offer a useful, detailed resource to deliver complex protocol-directed care.     

Genetic characterization of the fusidic acid and cadmium resistance determinants of Staphylococcus aureus plasmid pUB101

We report the cloning of the fusidic acid and cadmium resistance determinants from Staphylococcus aureus plasmid pUB101. The pUB101 fusidic acid resistance determinant was located on a 2.9 kb HindIII fragment. Sequencing of this fragment revealed three putative open reading frames (ORFs) of 213 (far1), 152 (orf152) and 170 amino acids (orf170), which are flanked by the right-hand end of insertion sequence IS431/257 (IS431/257RH) and a partial ORF. Far1 and Orf152 demonstrated homology with a chromosomally encoded fibronectin-binding protein of Listeria monocytogenes and the putative protein YosT, found on the SP beta c2 prophage of Bacillus subtilis, respectively. Transformation of S. aureus with a construct containing a 949 bp far1-specific amplicon led to the isolation of a fusidic acid-resistant transformant, thereby identifying the pUB101 fusidic acid resistance structural gene. Between orf152 and far1 we identified a unique 113 bp symmetrical element and other repeat elements that may be involved with the control of orf152 and/or far1 expression. Hybridization of Southern blots revealed that far1 was not located on the chromosome or plasmid content of a limited number of Australian, UK and Hong Kong fusidic acid-resistant isolates. The pUB101 cadmium resistance determinant was located on a 3.6 kb HindIII fragment that carried a cadDX operon, remnants of two putative plasmid replication protein genes and IS431/257RH. Sequence analysis also demonstrated the presence of a single-stranded origin of replication, normally found on rolling circle replicating plasmids, within the putative promoter region of the cadDX operon.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

Assessment of an electronic goniometer designed to measure equinus contracture

To achieve more objective and repeatable measurements of equinus contracture, we developed the equinometer, a device that allows the measurement of ankle range of motion under controlled torque conditions. This study assessed its accuracy across different subjects and examiners. Two examiners used the equinometer to measure the angle of ankle dorsiflexion at 15 N x m torque on five subjects. Accounting for variation in measurements because of subjects, examiners, and placement of device, we used linear mixed-effects models. Accounting for the variation because of subject, different placements of the equinometer within each subject and the adjustment for the effects of examiner and trial sequence, the standard deviation was 0.94 degrees, 95% confidence interval (0.79 degrees, 1.13 degrees). An upper standard deviation of 1.36 degrees is felt to be acceptable for clinical investigation.     

Multisubject fMRI studies and conjunction analyses.

In this paper we present an approach to making inferences about generic activations in groups of subjects using fMRI. In particular we suggest that activations common to all subjects reflect aspects of functional anatomy that may be "typical" of the population from which that group was sampled. These commonalities can be identified by a conjunction analysis of the activation effects in which the contrasts, testing for an activation, are specified separately for each subject. A conjunction is the joint refutation of multiple null hypotheses, in this instance, of no activation in any subject. The motivation behind this use of conjunctions is that fixed-effect analyses are generally more "sensitive" than equivalent random-effect analyses. This is because fixed-effect analyses can harness the large degrees of freedom and small scan-to-scan variability (relative to the variability in responses from subject to subject) when assessing the significance of an estimated response. The price one pays for the apparent sensitivity of fixed-effect analyses is that the ensuing inferences pertain to, and only to, the subjects studied. However, a conjunction analysis, using a fixed-effect model, allows one to infer: (i) that every subject studied activated and (ii) that at least a certain proportion of the population would have shown this effect. The second inference depends upon a meta-analytic formulation in terms of a confidence region for this proportion. This approach retains the sensitivity of fixed-effect analyses when the inference that only a substantial proportion of the population activates is sufficient.     

Multiple breath washout in pediatric patients after lung transplantation

Forced expiratory volume in 1 second (FEV₁) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen‐multiple breath washout (N₂‐MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (S_acin) airway inhomogeneity. We investigated whether N₂‐MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty‐seven children without bronchiolitis obliterans syndrome [BOS] at a median of 1.6 (0.6‐3.0) years after LTx underwent N₂‐MBW and spirometry, 28 of those on 2 occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS, LCI and S_acin were significantly elevated compared with healthy controls. LCI was abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV₁/forced vital capacity (FVC). Correlations of LCI with FEV₁/FVC (r = 0.1, P = .4) and FEV₁ (r = ?0.1, P = .6) were poor. N₂‐MBW represents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complementary physiologic measures.