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Biomedical subjects

J Wight

Publications and source records attributed to J Wight.

At least 19 recordsLinked to original sources
PubMed2003

The management of inhibitors in haemophilia A: introduction and systematic review of current practice.

Haemophilia is the commonest bleeding disorder in the UK, affecting approximately 5400 people, almost all of them male. In haemophiliacs, reduced levels, or absence, of factor VIII (FVIII) cause bleeding episodes, typically into joint spaces or muscles. Haemophilia is generally treated with exogenous FVIII. However, in some haemophiliacs, therapeutically administered FVIII comes to be recognized as a foreign protein, stimulating the production of antibodies (inhibitors), which react with FVIII to render it ineffective. Alternative treatment strategies then have to be used to manage bleeding episodes. In addition, strategies have been developed to attempt to abolish inhibitor production through the induction of immune tolerance. A systematic review was undertaken of current international practice for the clinical management of haemophilia A patients with inhibitors to FVIII, concentrating on literature published from 1995 onwards. Although it can be difficult to determine what constitutes current practice, current guidelines indicate that immune tolerance induction is seen as desirable, with the choice of regimen dependent on patient characteristics, familiarity with regimens and cost. Various approaches, based on similar factors, are used to control bleeding episodes.

Autoantibodies↗
PubMed2003

The epidemiology of inhibitors in haemophilia A: a systematic review.

This paper emphasizes the importance of distinguishing between the prevalence, incidence and cumulative incidence of inhibitors in haemophilia A. Incidence and cumulative incidence data will include patients with transient inhibitors or whose inhibitors have been eliminated by treatment. As these will not be included in prevalence data, prevalence studies will tend to give rise to lower figures than incidence studies. As a result, the most accurate estimates of the true risk of inhibitor development comes from prospective studies of newly diagnosed haemophiliacs who are tested regularly for the presence of inhibitors. This paper reports a systematic review of the best available evidence relating to the epidemiology of inhibitors in haemophilia A. Cohort studies, registry data reporting incidence or prevalence of inhibitors in patients with haemophilia A, and prospective studies of factor VIII (FVIII) in the treatment of previously untreated patients which reported the development of inhibitors as an outcome, were included in the review. The overall prevalence of inhibitors in unselected haemophiliac populations was found to be 5-7%. The cumulative risk of inhibitor development varied (0-39%). Incidence and prevalence were substantially higher in patients with severe haemophilia. Studies of patients using a single plasma-derived FVIII (pdFVIII) preparation reported lower inhibitor incidence than those using multiple pdFVIII preparations or single recombinant FVIII preparations. Incidence data should be used to estimate the likely demand for treatments aimed at eliminating inhibitors, whereas the best estimates of the overall burden to the National Health Service (NHS) of treating bleeding episodes in patients with continuing inhibitors will come from prevalence studies.

Autoantibodies↗
PubMed2003

Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review.

In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6-52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low-dose protocols. There is no good evidence that immunosuppressive drug regimens are effective.

Autoantibodies↗
PubMed2003

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

Acute Disease↗
PubMed2003

Economic modelling of different treatment strategies for haemophilia A with high-responding inhibitors.

This paper reports a systematic review of the cost-effectiveness of treatment options in patients with haemophilia A with inhibitors. As very little relevant published evidence was identified, an economic modelling exercise was undertaken to calculate the cost-effectiveness of different strategies in the treatment of high-responding haemophilia A patients with inhibitors. A decision analysis approach was used to model the expected lifetime clinical outcomes and costs of the more common regimens currently used in UK in treating severe haemophiliacs with inhibitors. The model attempts to reflect the outcomes of clinical events, costs and life expectancy for each different treatment regimen for haemophilic boys with inhibitors who are high responders (defined as inhibitor level >/=10 BU) throughout their life. The basic model structure is centred on a Markov decision process, which was used to simulate, at quarter-yearly intervals, the movement through discrete health states and their complications. The model allows a comparison of cost-effectiveness between three immune tolerance induction (ITI) regimens (Bonn, Mälmo and Low-Dose protocols) and against a relevant 'on-demand' (OD) regimen. It also shows the cost-effectiveness of different OD regimens using different bypassing agents. The results of the economic modelling indicate that treating haemophilia A patients who have high-responding inhibitors OD with recombinant activated factor VII is cost-effective compared to treatment with activated prothrombin complex concentrates. However, when OD treatment regimens are compared with the three ITI protocols, the Malmö ITI protocol is the preferred treatment strategy, generating more quality adjusted life-years (QALYs) and less cost than either an OD regimen or the Bonn or Low-Dose ITI protocols.

Cost-Benefit Analysis↗
PubMed2003

The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of machine perfusion (MP) compared to cold storage (CS), as a means of preserving kidneys prior to transplantation. Transplantation of kidneys from both heart-beating donors (HBDs) and non-heart-beating donors (NHBDs) is considered. Finally to review whether the use of MP can allow valid testing of kidney viability prior to transplantation. DATA SOURCES: Fifteen electronic bibliographic databases were searched. The reference lists of relevant articles and sponsor submissions were hand searched and various health service research-related resources were consulted via the Internet. REVIEW METHODS: A literature search was undertaken to identify relevant studies and a meta-analysis performed on the studies that had appropriate comparator groups and reported sufficient data. A structured review examined tests of viability of kidneys on MP. Economic modelling was used to determine the cost-effectiveness and cost-utility of MP. RESULTS: The meta-analysis suggested that the use of MP, as compared with CS, is associated with a relative risk of delayed graft function (DGF) of 0.804 (95% confidence limits 0.672 to 0.961). There was no evidence to suggest that this effect is different in kidneys taken from HBDs as opposed to NHBDs. Meta-analysis of 1-year graft survival data showed no significant effect, but the studies, even when aggregated, were severely underpowered with respect to the likely impact on graft survival. The size of effects demonstrated were in line with those predicted by an indirect model of graft survival based on the association of DGF with graft loss. The economic assessment indicated that it is unlikely that in the UK health setting complete cost recovery will be obtained from a reduction in the incidence of DGF. The probability that MP is cheaper and more effective than CS in the long term was estimated at around 80% for NHBD recipients and 50-60% for HBD recipients. Flow characteristics of the perfusate of kidneys undergoing MP may be an indicator of kidney viability, but data were inadequate to calculate the sensitivity and specificity of any test based on this. The concentration of alpha-glutathione-S-transferase (a marker of cell damage) in the perfusate may be the basis of a valid test. A threshold of 2800 micrograms/100 g gave a sensitivity of 93% and specificity of 33% (and hence a likelihood ratio of 1.41). CONCLUSIONS: The baseline analysis indicated that in the long-term MP would be expected to be cheaper and more effective than CS for both HBD and NHBD recipients. A definitive study of the clinical benefit of MP in order to establish its effect on DGF and longer term graft survival would be valuable, together with an economic evaluation of the benefits. While direct evidence relating to improvements in graft survival would be preferable, the small predicted improvement indicates that a very large sample size would be required. In addition to seeking direct evidence of the impact on DGF, research quantifying the impact of DGF on graft survival in this technology is required. Research is also needed to establish whether a valid test (or combination of tests) of kidney viability can be developed.

Cell Survival↗
PubMed2003

Treatments for spasticity and pain in multiple sclerosis: a systematic review.

OBJECTIVES: To identify the drug treatments currently available for the management of spasticity and pain in multiple sclerosis (MS), and to evaluate their clinical and cost-effectiveness. DATA SOURCES: Electronic bibliographic databases, National Research Register, MRC Clinical Trials Register and the US National Institutes of Health Clinical Trials Register. REVIEW METHODS: Systematic searches identified 15 interventions for the treatment of spasticity and 15 interventions for treatment of pain. The quality and outcomes of the studies were evaluated. Reviews of the treatment of spasticity and pain when due to other aetiologies were also sought. RESULTS: There is limited evidence of the effectiveness of four oral drugs for spasticity: baclofen, dantrolene, diazepam and tizanidine. Tizanidine appears to be no more effective than comparator drugs such as baclofen and has a slightly different side-effects profile. Despite claims that it causes less muscle weakness, there was very little evidence that tizanidine performed any better in this respect than other drugs, although it is more expensive. The findings of this review are consistent with reviews of the same treatments for spasticity derived from other aetiologies. There is good evidence that both botulinum toxin (BT) and intrathecal baclofen are effective in reducing spasticity, and both are associated with functional benefit. However, they are invasive, and substantially more expensive. None of the studies included in the review of pain were designed specifically to evaluate the alleviation of pain in patients with MS and there was no consistency regarding the use of validated outcome measures. It was suggested that, although expensive, the use of intrathecal baclofen may be associated with significant savings in hospitalisation costs in relation to bed-bound patients who are at risk of developing pressure sores, thus enhancing its cost-effectiveness. No studies of cost-effectiveness were identified in the review of pain. There is evidence, albeit limited, of the clinical effectiveness of baclofen, dantrolene, diazepam, tizanidine, intrathecal baclofen and BT and of the potential cost-effectiveness of intrathecal baclofen in the treatment of spasticity in MS. CONCLUSIONS: Many of the interventions identified are not licensed for the alleviation of pain or spasticity in MS and the lack of evidence relating to their effectiveness may also limit their widespread use. Indeed, forthcoming information relating to the use of cannabinoids in MS may result in there being better evidence of the effectiveness of new treatments than of any of the currently used drugs. It may therefore be of value to carry out double-blind randomised controlled trials of interventions used in current practice, where outcomes could include functional benefit and impact on quality of life. Further research into the development and validation of outcomes measures for pain and spasticity may also be useful, as perhaps would cost-utility studies.

Adolescent↗
PubMed2002

Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review.

Spasticity is a common disabling feature of multiple sderosis. A variety of drugs are in regular use as oral treatment induding badofen, dantrolene, tizanidine, and diazepam. Published evidence of effectiveness is limited. Most trials are of small size, of short duration, and have not reported on functional outcomes. Studies have been published which suggest that badofen, tizanidine, and diazepam are all effective in reducing dinical measures of spasticity, but there is little evidence that they lead to an improvement in patient function. There is no evidence to suggest any difference in effectiveness between them. The evidence that dantrolene has any effect on spasticity is of poor quality. Diazepam and dantrolene are associated with more side effects than baclofen and tizanidine. There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value. One randomized controlled trial of threonine does not support its effectiveness.

Administration, Oral↗
PubMed1998

Divergent effects of angiotensin-converting enzyme inhibition and angiotensin II-receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats.

There is mechanistic rationale to suggest differential effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1)-receptor antagonism on ventricular remodeling after myocardial infarction (MI). We compared the effects of ACE inhibition, AT1-receptor antagonism, and their combination on post-MI ventricular remodeling in rats. We induced MI in 62 rats, which then received one of four treatments: (a) placebo; (b) the ACE inhibitor, enalapril; (c) the AT1-receptor antagonist, losartan; and (d) enalapril and losartan in combination. Two weeks after MI, we examined: (a) heart weight (HW)/body weight (BW) ratio; (b) nonmyocyte cellular proliferation in the noninfarct zone by using proliferating cell nuclear antigen staining; and (c) collagen content within the noninfarct zone. Placebo-treated, infarcted rats developed significant increases in HW/BW ratio (p < 0.001), left ventricular (LV) volume (p < 0.01), nonmyocyte cellular proliferation (p < 0.04), and collagen content (p < 0.01) compared with noninfarcted controls. Enalapril, losartan, and combination therapy limited the increase in HW/BW ratio (all p values <0.01 vs. placebo). Enalapril inhibited nonmyocyte proliferation (p < 0.01 vs. placebo), whereas losartan had a smaller effect (p = NS vs. placebo; p < 0.03 vs. enalapril); combined treatment also reduced nonmyocyte cellular proliferation but did not reach statistical significance (p = 0.08 vs. placebo). Enalapril and combination treatment significantly diminished collagen content (both p values <0.01 vs. placebo), whereas losartan did not. Thus, ACE inhibition and AT1-receptor antagonism equally limited myocardial hypertrophy after MI in rats, but ACE inhibition more effectively prevented nonmyocyte cellular proliferation and collagen deposition in the noninfarcted myocardium. Combination therapy was no more effective than was ACE inhibition alone. These data suggest that the myocyte hypertrophic response after MI is strongly influenced by activation of the AT1 receptor, whereas nonmyocyte cellular proliferation and collagen deposition result, in part, from mechanisms separate from AT1-receptor activation.

Angiotensin Receptor Antagonists↗
PubMed1998

Clinical reasoning case studies as teaching tools.

OBJECTIVE: Students are taught how to apply clinical reasoning methods through a variety of teaching methods, including the use of case studies. Various types of case studies have been described in the literature: paper cases, videotape cases, simulated client cases, and real client cases. This study examined the effectiveness of a new type of paper case study--the clinical reasoning case study--in teaching the clinical reasoning process to occupational therapy students. METHOD: Four seniors in an undergraduate occupational therapy program completed intervention plans in response to both traditional medical model and clinical reasoning paper case studies. Qualitative methods were used to analyze intervention plans and videotaped discussion about this learning experience. RESULTS: Themes discovered in the data sources suggest that compared with traditional case studies, the clinical reasoning case studies increased the quality of participants' intervention plans, participants' confidence levels about their plans, and participants' understanding of the clinical reasoning process. Participants also reported preferring clinical reasoning case studies over traditional paper case studies. CONCLUSION: The clinical reasoning case studies are effective teaching tools because they provide students with a holistic picture of the client and his or her occupational therapy treatment. In addition, these case studies model the clinical reasoning process by organizing client information according to the types of clinical reasoning that would be used to gather that information. Occupational therapy educators may find this type of paper case study useful in introducing students to the intervention planning process.

Female↗
PubMed1996

A computer model for predicting the demand for end-stage renal failure (ESRF) treatment, contract setting and monitoring.

BACKGROUND: The high cost of end-stage renal failure (ESRF) treatment, and the anticipated need for expansion of the service at a time of limited resources for health care expenditure, means that careful planning of such an expansion is necessary. This needs to inform the setting and monitoring of contracts between commissioning organizations and providers of treatment. A spreadsheet based computer model is described which fulfils both of these needs. METHODS: A computer programme was written to run on a commonly available spreadsheet in order to predict the demand for ESRF treatment, set contracts, and monitor in year performance. RESULTS: The model described has facilitated contracting for ESRF services. Purchasers have used it to examine various planning scenarios, while the provider unit has used it to support a business case for further development. Using this model, the predictions for the Sheffield resident population are that the total number of patients on the ESRF treatment programme will increase from a mid-year average of 204 patients in the year 1994-95 to 266 patients in the year 1999-2000, while costs increased over the same time period from 2.37 million pounds to 2.78 million pounds. CONCLUSIONS: A computer spreadsheet based model described is a useful tool for predicting demand, and setting and monitoring contracts, for treatment for ESRF. Problems with the model and potential further developments are discussed.

Competitive Bidding↗