Psychological interventions improve quality of life despite persistent pain in endometriosis: results of a 3-armed randomized controlled trial.

PURPOSE: Despite standard medical treatment endometriosis is often associated with disabling pain and poor quality of life (QoL). Studies indicate that psychological interventions (PIs) may improve pain and QoL, yet studies on the effects of PIs for women with endometriosis are sparse and limited by low-quality study designs. Therefore, this study aimed, in a rigorous three-armed design, to evaluate the effect of PIs on chronic pelvic pain (CPP) and QoL in women with endometriosis. METHODS: This three-armed parallel, multi-center randomized controlled trial included fifty-eight endometriosis patients reporting severe CPP [≥ 5 for pain intensity measured on a 0-10-point numeric rating scale (NRS)]. Patients were randomly assigned to (1) Specific mindfulness- and acceptance-based psychological intervention (MY-ENDO), (2) Carefully matched non-specific psychological intervention (Non-specific), or (3) A wait-list control group (WL). The primary outcome was pelvic pain intensity/unpleasantness measured on NRS. Secondary outcomes included endometriosis-related quality of life, workability, pain acceptance, and endometriosis-related symptoms. Differences in outcomes between groups at post-treatment follow-up were analyzed using mixed linear models. Analyses were performed on an intention-to-treat basis. RESULTS: Compared to WL, psychological intervention (MY-ENDO + Non-specific) did not significantly reduce pain. However, psychological intervention did significantly improve the QoL-subscales 'control and powerlessness', 'emotional well-being', and 'social support' as well as the endometriosis-related symptoms 'dyschezia' and 'constipation'. MY-ENDO was not superior to Non-specific. CONCLUSIONS: Women with endometriosis may have significant and large effects of psychological intervention on QoL despite an ongoing experience of severe CPP. TRIAL REGISTRATION: 12 April 2016, clinicaltrials.gov (NCT02761382), retrospectively registered.

Bowel Endometriosis Syndrome: a new scoring system for pelvic organ dysfunction and quality of life.

STUDY QUESTION: Is it possible to develop a validated score that can identify women with Bowel Endometriosis Syndrome (BENS) and be used to monitor the effect of medical and surgical treatment? SUMMARY ANSWER: The BENS score can be used to identify women with BENS and to monitor the effect of medical and surgical treatment of women suffering from bowel endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a heterogeneous disease with extensive variation in anatomical and clinical presentation, and symptoms do not always correspond to the disease burden. Current endometriosis scoring systems are mainly based on anatomical and surgical findings. STUDY DESIGN, SIZE, DURATION: The score was developed and validated from a cohort of 525 women with medically or surgically treated bowel endometriosis from Aarhus and Copenhagen University Hospitals, Denmark. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Patients filled in questionnaires on pelvic pain, quality of life (QoL) and urinary, sexual and bowel function. Items were selected for the final score using clinical and statistical criteria. The chosen variables were included in a multivariate analysis. Individual score values were designated items to form the BENS score, which was divided into 'no BENS', 'minor BENS' and 'major BENS.' Internal and external validations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The six most important items were 'pelvic pain', 'use of analgesics', 'dyschezia', 'straining to urinate', 'fecal urgency' and 'satisfaction with sexual life'. The range of the BENS score (0-28) was divided into 0-8 (no BENS), 9-16 (minor BENS) and 17-28 (major BENS). External validation showed a significant association between BENS score and QoL (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The BENS scoring system is limited by the fact that it was developed from a single endometriosis unit in Denmark, making it susceptible to social, cultural and demographic bias. WIDER IMPLICATIONS OF THE FINDINGS: It is the first endometriosis classification system to be based directly on the symptomatology of the patient. Validation in other languages will promote comparison of treatments and results across borders. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study. A.F. is an investigator for Bayer, outside this work.

Using process data to understand outcomes in sexual health promotion: an example from a review of school-based programmes to prevent sexually transmitted infections.

This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills-based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model.

Reproductive prognosis in daughters of women with and without endometriosis.

STUDY QUESTION: Do daughters of women with endometriosis exhibit an increased risk of endometriosis and impaired long-term reproductive prognosis when compared with daughters of women without endometriosis? SUMMARY ANSWER: Daughters of women with endometriosis have over a 2-fold higher risk of endometriosis but no difference in long-term reproductive prognosis compared with controls. WHAT IS KNOWN ALREADY: Several studies have found an increased prevalence of endometriosis in sisters and mothers of women with endometriosis, but none have examined the long-term reproductive prognosis in daughters of these patients. STUDY DESIGN, SIZE, DURATION: A controlled historical cohort study with a 33-year follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among women 15-49 years old during the period 1977-1982, 24 691 were diagnosed with endometriosis during the study period. These women were age matched to 98 764 women without endometriosis. Daughters of these two groups were followed until 31 December 2009 for an endometriosis diagnosis and reproductive outcomes. Women were excluded from the study at death or if they emigrated. MAIN RESULTS AND THE ROLE OF CHANCE: Except for 4-6% of emigrated women, the follow-up rate of the study was almost 100%. Daughters of women with endometriosis (n = 12 389) had a 2.12-fold (95% confidence interval 1.89-2.37, P < 0.0001) increased risk of being diagnosed with endometriosis, compared with daughters of women without endometriosis (n = 52 371). Delivery rate, risk of spontaneous abortions and ectopic pregnancies were similar for the two cohorts, whereas induced abortions were slightly more frequent in the exposed cohort. LIMITATIONS, REASONS FOR CAUTION: The most important limitation of the study was the lack of data concerning the attempt to become pregnant. Also, some women with endometriosis might never be diagnosed with the condition. This applies to both the control mothers and the control daughters, but also the daughters of mothers with endometriosis. Other limitations are lack of accounting for potential confounders and the lack of data on preterm birth. However, the influence of most confounding factors was expected to be minimal because of the close matching by age of controls. WIDER IMPLICATIONS OF THE FINDINGS: The external validity of the study is expected to be high owing to the unselected inclusion criteria. The encouraging finding was that despite the increased risk of being diagnosed with endometriosis, daughters of women with endometriosis have a reproductive prognosis comparable with that of daughters of women without endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The Department of Gynaecology at Rigshospitalet University Hospital, Copenhagen, covered all expenses of the study. Ø.L. has, within the last 3 years, received honoraria for speeches in pharmacoepidemiological issues and has been expert witness in a legal US case in 2011-2012. None of the other authors have any conflicts of interest.

Role of P-selectin cytoplasmic domain in granular targeting in vivo and in early inflammatory responses.

P-selectin is an adhesion receptor for leukocytes expressed on activated platelets and endothelial cells. The cytoplasmic domain of P-selectin was shown in vitro to contain signals required for both the sorting of this protein into storage granules and its internalization from the plasma membrane. To evaluate in vivo the role of the regulated secretion of P-selectin, we have generated a mouse that expresses P-selectin lacking the cytoplasmic domain (DeltaCT mice). The deletion did not affect the sorting of P-selectin into alpha-granules of platelets but severely compromised the storage of P-selectin in endothelial cells. Unstored P-selectin was proteolytically shed from the plasma membrane, resulting in increased levels of soluble P-selectin in the plasma. The DeltaCT-P-selectin appeared capable of mediating cell adhesion as it supported leukocyte rolling in the mutant mice. However, a secretagogue failed to upregulate leukocyte rolling in the DeltaCT mice, indicating an absence of a releasable storage pool of P-selectin in the endothelium. Furthermore, the neutrophil influx into the inflamed peritoneum was only 30% of the wild-type level 2 h after stimulation. Our results suggest that different sorting mechanisms for P-selectin are used in platelets and endothelial cells and that the storage pool of P-selectin in endothelial cells is functionally important during early stages of inflammation.

Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.

Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

OBJECTIVES: To review the clinical evidence comparing immediate angioplasty with thrombolysis, and to consider whether it would be cost-effective. DATA SOURCES: Electronic databases. Experts in the field. REVIEW METHODS: For clinical effectiveness, a comprehensive review of randomised control trials (RCTs) was used for efficacy, and a selection of observational studies such as case series or audit data used for effectiveness in routine practice. RCTs of thrombolysis were used to assess the relative value of prehospital and hospital thrombolysis. Observational studies were used to assess the representativeness of patients in the RCTs, and to determine whether different groups have different capacity to benefit. Clinical effectiveness was synthesised through a narrative review with full tabulation of results of all included studies and a meta-analysis to provide a precise estimate of absolute clinical benefit. Consideration was given to the effect of the growing use of stents. The economic modelling adopted an NHS perspective to develop a decision-analytical model of cost-effectiveness focusing on opportunity costs over the short term (6 months). RESULTS: The results were consistent in showing an advantage of immediate angioplasty over hospital thrombolysis. The updated meta-analysis showed that mortality is reduced by about one-third, from 7.6% to 4.9% in the first 6 months, and by about the same in studies of up to 24 months. Reinfarction is reduced by over half, from 7.6% to 3.1%. Stroke is reduced by about two-thirds, from 2.3% with thrombolysis to 0.7% with percutaneous coronary intervention (PCI), with the difference being due to haemorrhagic stroke. The need for coronary artery bypass graft is reduced by about one-third, from 13.2% to 8.4%. Caution is needed in interpreting some of the older trials, as changes such as an increase in stenting and the use of the glycoprotein IIb/IIa inhibitors may improve the results of PCI. There is little evidence comparing prehospital thrombolysis with immediate PCI. Research on thrombolysis followed by PCI, known as 'facilitated PCI', is underway, but results are not yet available. Trials may be done in select centres and results may not be as good in lower volume centres, or out of normal working hours. In addition, much of the marginal mortality benefit of PCI over hospital thrombolysis may be lost if door-to-balloon time were more than an hour longer than door-to-needle time. Conversely, within the initial 6 hours, the later patients present, the greater the relative advantage of PCI. Results suggest that PCI is more cost-effective than thrombolysis, providing additional benefits in health status at some extra cost. In the longer term, the cost difference is expected to be reduced because of higher recurrence and reintervention rates among those who had thrombolysis. CONCLUSIONS: If both interventions were routinely available, the economic analysis favours PCI, given the assumptions of the model. However, very few units in England could offer a routine immediate PCI service at present, and there would be considerable resource implications of setting up such services. Without a detailed survey of existing provision, it is not possible to quantify the implications, but they include both capital and revenue: an increase in catheter laboratory provision and running costs. The greatest problem would be staffing, and that would take some years to resolve. A gradual incrementalist approach based on clinical networks, with transfer to centres able to offer PCI, may be used. In rural areas, one option may be to promote an increase in prehospital thrombolysis, with PCI for thrombolysis failures. There is a need for data on the long-term consequences of treatment, the quality of life of patients after treatment, and the effects of PCI following thrombolysis failure.

Aberrant cytokine regulation in macrophages from young autoimmune-prone mice: evidence that the intrinsic defect in MRL macrophage IL-1 expression is transcriptionally controlled.

We have reported that, when compared to macrophages from normal strains, macrophages from the autoimmune-prone MRL and NZB mouse strains demonstrate dramatically reduced IL-1 expression in response to LPS. In MRL mice, this is an intrinsic defect which is unmodified by age, the progression of disease, or the presence of the Ipr gene. Here we report that the key events leading to aberrant IL-1 expression appear to be transcriptional, based on the following three sets of findings. (1) Nuclear run-on analysis demonstrates that the patterns of IL-1 transcription in MRL/+ and BALB/c macrophages are distinct, as the former is clearly more transient. The reduction in MRL/+ IL-1 transcription coincides with a reduction in the levels of nuclear NF-KB and precedes a drop in IL-1 mRNA steady-state levels. (2) Reduced levels of IL-1 transcripts are found in both nuclear and cytosolic fractions of MRL/+ macrophages, arguing against faculty IL-1 mRNA transport into the cytosol as a contributing factor in the establishment of this defect. (3) In the presence of actinomycin D, the rate of RNA degradation is similar in MRL/+ and BALB/c macrophages. Moreover, in vitro RNA decay assays demonstrate that even in the absence of metabolic inhibitors, there is no evidence for an accelerated decay of IL-1 mRNA during exposure to lysates isolated from MRL/+ vs BALB/c macrophages. Taken together, these findings argue that transcription is the predominant level at which this striking example of cytokine dysregulation is controlled.

Changes in vitamin D metabolism during natural and medical menopause.

Thirty-nine women were studied longitudinally for 3 yr, during which period 10 women passed a natural menopause. Vitamin D metabolites were determined every 3 months in these 10 women. The same variables were studied in 42 premenopausal women with endometriosis treated for 6 months with nafarelin acetate (a LHRH agonist) given alone in a dose of 200 or 400 micrograms or in a dose of 400 micrograms combined with 1.2 mg norethisterone (NET)/day and followed-up for a further 6 months. No changes were seen in 1,25-dihydroxyvitamin D [1,25-(OH)2D], vitamin D-binding protein, or the free index of 1,25-(OH)2D during the natural menopause. A small increase was found in 25-hydroxyvitamin D [25OHD] and 24,25-(OH)2D3 after correction for seasonal variation. All three nafarelin groups had a significantly decreased free index of 1,25-(OH)2D, which returned to the baseline value on withdrawal of the treatment. Serum 25OHD and 24,25-(OH)2D3 were increased at 6 months and thereafter decreased to baseline values. These changes were still visible after correction for seasonal variation. Vitamin D-binding protein showed a small transient increase in the nafarelin plus NET group, but was unchanged in the other two groups. The 24-h urinary excretion of calcium increased significantly in the groups receiving nafarelin alone, whereas it remained unchanged in the nafarelin plus NET group. We conclude that detectable changes in 1,25-(OH)2D do not occur in natural menopause. Treatment with LHRH agonists produces a significant decrease in serum 1,25-(OH)2D, which does not seem to be dependent on increased bone resorption. This suggests that LHRH agonists may induce a change in other pituitary hormones involved in vitamin D regulation.

Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I, and serum testosterone.

Serum bone Gla-protein (BGP) was determined by RIA in 450 normal children (229 girls and 221 boys, aged 6-19 yr). Serum BGP concentrations changed in relation to age and sex with a pattern that resembles the height velocity curves for children. The increase in serum BGP occurred at the expected age of the growth spurt in both sexes, and the peak values occurred at the age of 12 yr in girls [mean, 49.2 +/- 5.6 (+/- SE) micrograms/L] and 14 yr in boys (64.0 +/- 6.3 micrograms/L). In the boys aged 10-14 yr and in the girls aged 9-12 yr, serum BGP correlated significantly with serum insulin-like growth factor I (IGF-I), serum testosterone, age and height. When the interrelationship was analyzed by means of partial correlation, with age held constant, serum BGP still correlated significantly with the other parameters, but when height was fixed there was only a correlation with serum IGF-I. In children with untreated central precocious puberty, the mean serum BGP concentration was significantly higher than in age-matched normal children [mean, 61.4 +/- 31.7 (+/- SD) vs. 29.0 +/- 10.3 micrograms/L; P less than 0.001]. Serum BGP values decreased significantly in these patients during 1 yr of treatment with a LHRH analog (buserelin) and cyproterone acetate. We conclude that serum BGP is a sensitive marker of bone growth in normal children and in children with increased growth velocity. Repeated measurements may provide useful information in the diagnosis and treatment of children with disturbances in bone turnover.

New discoveries with mice mutant in endothelial and platelet selectins.

Genetically engineered mice bring animal studies to the molecular level in that they help establish the role of a particular molecule, or its portion, in a complex biological process. In recent years, several discoveries were made using the selectin-mutant mice. For example, it was shown that these molecules not only mediate leukocyte rolling, but also platelet rolling on the vessel wall. The functional significance of platelet rolling has yet to be uncovered. The process could be important for hemostasis leading to firm platelet adhesion at sites of denuded endothelium and/or in inflammation. After activation, platelets may help in leukocyte recruitment as shown by studies of lymphocyte homing to peripheral lymph nodes. Surprisingly, work with the P-selectin mutant mice has also revealed an anti-inflammatory aspect of platelet P-selectin. P-selectin binding to leukocytes promoted the transcellular production of an anti-inflammatory mediator limiting the extent of acute glomeluronephritis. In addition, soluble P-selectin was shown recently to be shed from both activated platelets and endothelium and there are strong indications that it too could have an attenuating effect on inflammatory disease progression. Another discovery made with the selectin-deficient mice is on the crucial role of P- and E-selectins in the homing of hematopoietic progenitor cells to the bone marrow. This observation could perhaps be further exploited by use of selectin inhibitors when liberating the progenitors from the marrow for transplant purposes. The use of selectin inhibitors could also be evaluated in two major disease processes where selectins were recently shown to play a role: cancer and atherosclerosis. Thus the selectin mutant mice have taught us a great deal about the role of selectins in normal physiology and in pathology. Further studies are needed to explore the regulation of shedding of the selectins and the function of soluble selectins in vivo. Exploring new territories of selectin-mediated interactions may provide a basis for developing new interventions and treatments for diseases in which the role of selectins has not yet been suspected.

Imbalanced cytokine production by macrophages from autoimmune-prone mice.

Peritoneal macrophages from multiple autoimmune-prone strains of mice (MRL/lpr, MRL/+, NZB/W, BXSB, and B6/gld) show defective expression of the cytokines IL-1 and IL-6. Autoimmune mice were all used between 1 and 6 weeks of age, the earliest times being well before the onset of overt disease. Northern blot analysis reveals a parallel reduction in the levels of IL-1 alpha, IL-1 beta, and IL-6 mRNA. In contrast, the production of other proteins, including the cytokine TNF-alpha, appears to be normal. These findings imply an imbalance within the cytokine network of autoimmune macrophages. Studies on bone marrow-derived macrophage precursors, as well as macrophages from chimeric mice, suggest an intrinsic macrophage defect as opposed to conditioning by the autoimmune environment. This defect appears to be constant throughout the lifespan of autoimmune MRL/lpr mice, being equally apparent in 1-week old mice as in fully diseased 6-12-month-old mice. Aberrant regulation of IL-1 and IL-6 represents a novel defect in the function of autoimmune macrophages that is both intrinsic and substantial, and has the potential to contribute to the immune dysregulation that characterizes autoimmunity.

Cytokine dysregulation and the initiation of systemic autoimmunity.

Autoimmunity (AI) exemplifies the potent and destructive activity expressed by the immune system when normal constraints against self-reactivity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) from young AI-prone mice [1-3]. There are two points in particular that we believe speak to the importance of this observation: (i) Cytokine dysregulation is distinguished from many of the aberrancies reported in AI-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarkably consistent characteristic of M phi from strains that develop manifestations of systemic AI, including MRL/+, NZB, NZB/W F1, BXSB, and NOD, and distinguishes these strains from mice whose disease is predicated on defects in apoptosis (e.g., the lpr and gld mutations). The multigenic basis for disease and renal pathology in the former strains more closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key mediators of lymphocyte growth and function, a defect in the cytokine network has the potential to disrupt the normal regulation of self-reactivity, leading to the initiation of systemic AI.

Dysregulated cytokine expression in vivo in prediseased and diseased autoimmune-prone MRL mice.

Macrophages (mø) from prediseased autoimmune-prone MRL/ + and MRL/lpr mice produce markedly decreased levels of IL-1 in vitro in response to LPS. In contrast, tissues from diseased MRL/lpr mice overexpress IL-1 in vivo. To determine whether IL-1 underproduction in the MRL strains is solely an in vitro phenomenon, we compared in vivo cytokine mRNA expression from prediseased age-matched MRL/ + and MRL/lpr mice to that from normal BALB/c and C3HeB/FeJ mice. Like mø in vitro, whole organ RNA from the spleen, liver, and kidney of MRL/ + and MRL/lpr mice showed down-regulation of IL-1 RNA following intraperitoneal injection of LPS. This abnormality in inducible IL-1 expression was present in all MRL mice, irrespective of disease stage or the presence of the lpr gene. On the other hand, only diseased MRL/lpr mice displayed elevated and constitutive expression of IL-1 in their livers and kidneys. We suggest that inducible expression is most indicative of the intrinsic, or genetic, capacity of cells to produce cytokine, whereas constitutive expression reflects extracellular disease-related inflammatory stimuli present only in the diseased MRL/lpr strains. By restricting our studies to prediseased MRL mice, we have tried to eliminate the effects of disease and to focus on the predisposing genetic background. The existence both in vitro and in vivo of a defect in inducible IL-1 expression by prediseased MRL mice suggests that the molecular abnormality underlying this defect may be a part of this predisposing background to autoimmunity.

Soluble P-selectin moderates complement dependent injury.

P-selectin is an adhesion molecule expressed on activated endothelial and platelet membranes containing 9 short consensus repeats (SCRs) similar to the composition of complement regulatory proteins. In our murine model of intestinal ischemia and reperfusion where local injury is mediated by the classical complement pathway we hypothesized the SCRs would moderate the complement response. Confirmatory data were sought following hindlimb ischemia and reperfusion where injury is both complement- and neutrophil-mediated. Mice deficient in P-selectin (P-/-) were found to have similar intestinal and hindlimb permeability compared to normal wild types mice (P+/+). When reconstituted with P+/+ platelets, but not P-/- platelets, P-/- mice subjected to intestinal ischemia had a significant 29% decrease in permeability (P < 0.05) and after hindlimb ischemia the decrease was 33% (P<0.05). Reperfusion after intestinal ischemia led to a 76% fall in CH50 in P-/- compared to sham animals (P < 0.05) indicating complement activation and consumption, but only a 36% fall in animals reconstituted with P+/+ platelets (P < 0.05). Full-length, soluble P-selectin (sPsel) derived from processed platelets, but not the truncated version of sPsel has been shown to adhere to a heat labile fraction of serum and sensitized red blood cells thereby reducing Clq adherence to the sensitized red cell. From these data we conclude that sPsel moderates complement activation by competing with C1q binding to antibody, thereby limiting activation of the classical pathway that mediates murine reperfusion injury.

Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

OBJECTIVES: To assess the clinical and cost-effectiveness of continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) in the delivery of intensive insulin therapy for the treatment of diabetes mellitus. DATA SOURCES: Electronic databases, references of retrieved articles and manufacturer submissions. Experts in the field were consulted. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Data on clinical effectiveness were synthesised through a narrative review with full tabulation of all eligible studies, with meta-analysis performed where appropriate. RESULTS: Twenty studies comparing CSII with MDI were identified. Quality was generally poor. In adults with Type 1 diabetes, glycated haemoglobin improved by 0.61% (95% CI -1.29 to 0.07) in longer term studies, although this improvement was smaller when a study using bovine ultralente was excluded. A reduction in insulin dose with CSII of about 12 units per day (-11.90, 95% CI -18.16 to 5.63) was found in short-term studies, with smaller differences in longer term studies. Body weight and cholesterol levels were similar between treatments. Hypoglycaemic events did not differ significantly between CSII and MDI in most trials, but some found fewer events with CSII and one found more hypoglycaemia and hypoglycaemic coma with CSII. There was no consistency between the studies in patient preference, but progress has been made both with insulin pumps and injector pens since the publication of many of the older studies. No difference in glycated haemoglobin between CSII and MDI was found in pregnancy; one study found less insulin was required by patients with CSII, but two other studies found no significant difference. One study of adolescents found lower glycated haemoglobin and insulin dose with CSII whereas a second study found no significant difference. In CSII analogue insulin was associated with lower glycated haemoglobin levels than soluble insulin. No economic evaluations comparing CSII with MDI were identified. The estimated additional cost of CSII compared to MDI varies from GBP1091 per annum to GBP1680 per annum, according to the make of the insulin pump and the estimated life of the device. These estimates include the costs for the insulin pump, the consumables associated with delivery of CSII, and an allowance for the initial education required when patients switch from MDI to CSII. The largest component of the annual cost for CSII is the cost of consumable items (e.g. infusion sets). CONCLUSIONS: When compared with optimised MDI, CSII results in a modest but worthwhile improvement in glycated haemoglobin in adults with Type 1 diabetes. It has not been possible to establish the longer term benefits of such a difference in glycated haemoglobin, although there is an expectation that it would be reflected in a reduction in long-term complications. More immediate primary benefits from CSII may be associated with an impact on the incidence of hypoglycaemic events and the dawn phenomenon, and greater flexibility of lifestyle. However, there is limited evidence on this, and information presented to offer context on quality-of-life is based on testimonies from those patients who have had a positive experience of CSII. The estimated cost to the NHS per year for CSII would be around GBP3.5 million in England and Wales if 1% of people with Type 1 diabetes used CSII, GBP10.5 million for 3%, and GBP17.5 million for 5%. Further research should focus on wider benefits of CSII, such as flexibility of lifestyle and quality of life, and on the psychological impact of wearing a device for 24 hours every day. Research into the use of CSII in children of different ages is also needed.

Low-cost high-fidelity anaesthetic simulation.

Simulation has been advocated as a useful training tool, and specific manikin simulators have been developed for use in this role. Debriefing and repetition have been identified as key to achieving educational goals and, while the technical features of manikin simulators can influence simulation outcomes, their cost and infrastructure requirements reduce their suitability for smaller healthcare facilities. We describe a local solution using biomedical calibration machines and modified basic manikins already available in our institution to form a high-fidelity anaesthetic simulator at minimal cost. This was effective in running high-fidelity, team-based in situ simulations and 'can't intubate, can't oxygenate' assessments for anaesthetic trainees. Though equipment in other centres may differ both in availability or suitability for simulation, the option we describe or similar may offer a low-cost solution for peripheral centres to run limited high-fidelity scenarios on a regular basis.

The effectiveness of interventions to treat severe acute malnutrition in young children: a systematic review.

BACKGROUND: Severe acute malnutrition (SAM) arises as a consequence of a sudden period of food shortage and is associated with loss of a person's body fat and wasting of their skeletal muscle. Many of those affected are already undernourished and are often susceptible to disease. Infants and young children are the most vulnerable as they require extra nutrition for growth and development, have comparatively limited energy reserves and depend on others. Undernutrition can have drastic and wide-ranging consequences for the child's development and survival in the short and long term. Despite efforts made to treat SAM through different interventions and programmes, it continues to cause unacceptably high levels of mortality and morbidity. Uncertainty remains as to the most effective methods to treat severe acute malnutrition in young children. OBJECTIVES: To evaluate the effectiveness of interventions to treat infants and children aged < 5 years who have SAM. DATA SOURCES: Eight databases (MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, CAB Abstracts Ovid, Bioline, Centre for Reviews and Dissemination, EconLit EBSCO and The Cochrane Library) were searched to 2010. Bibliographies of included articles and grey literature sources were also searched. The project expert advisory group was asked to identify additional published and unpublished references. REVIEW METHODS: Prior to the systematic review, a Delphi process involving international experts prioritised the research questions. Searches were conducted and two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full texts of retrieved papers by one reviewer and checked independently by a second. Included studies were mapped to the research questions. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. Studies were synthesised through a narrative review with tabulation of the results. RESULTS: A total of 8954 records were screened, 224 full-text articles were retrieved, and 74 articles (describing 68 studies) met the inclusion criteria and were mapped. No evidence focused on treatment of children with SAM who were human immunodeficiency virus sero-positive, and no good-quality or adequately reported studies assessed treatments for SAM among infants < 6 months old. One randomised controlled trial investigated fluid resuscitation solutions for shock, with none adequately treating shock. Children with acute diarrhoea benefited from the use of hypo-osmolar oral rehydration solution (H-ORS) compared with the standard World Health Organization-oral rehydration solution (WHO-ORS). WHO-ORS was not significantly different from rehydration solution for malnutrition (ReSoMal), but the safety of ReSoMal was uncertain. A rice-based ORS was more beneficial than glucose-based ORSs, and provision of zinc plus a WHO-ORS had a favourable impact on diarrhoea and need for ORS. Comparisons of different diets in children with persistent diarrhoea produced conflicting findings. For treating infection, comparison of amoxicillin with ceftriaxone during inpatient therapy, and routine provision of antibiotics for 7 days versus no antibiotics during outpatient therapy of uncomplicated SAM, found that neither had a significant effect on recovery at the end of follow-up. No evidence mapped to the next three questions on factors that affect sustainability of programmes, long-term survival and readmission rates, the clinical effectiveness of management strategies for treating children with comorbidities such as tuberculosis and Helicobacter pylori infection and the factors that limit the full implementation of treatment programmes. Comparison of treatment for SAM in different settings showed that children receiving inpatient care appear to do as well as those in ambulatory or home settings on anthropometric measures and response time to treatment. Longer-term follow-up showed limited differences between the different settings. The majority of evidence on methods for correcting micronutrient deficiencies considered zinc supplements; however, trials were heterogeneous and a firm conclusion about zinc was not reached. There was limited evidence on either supplementary potassium or nicotinic acid (each produced some benefits), and nucleotides (not associated with benefits). Evidence was identified for four of the five remaining questions, but not assessed because of resource limitation. LIMITATIONS: The systematic review focused on key questions prioritised through a Delphi study and, as a consequence, did not encompass all elements in the management of SAM. In focusing on evidence from controlled studies with the most rigorous designs that were published in the English language, the systematic review may have excluded other forms of evidence. The systematic review identified several limitations in the evidence base for assessing the effectiveness of interventions for treating young children with severe acute malnutrition, including a lack of studies assessing the different interventions; limited details of study methods used; short follow-up post intervention or discharge; and heterogeneity in participants, interventions, settings, and outcome measures affecting generalisability. CONCLUSIONS: For many of the most highly ranked questions evidence was lacking or inconclusive. More research is needed on a range of topic areas concerning the treatment of infants and children with SAM. Further research is required on most aspects of the management of SAM in children < 5 years, including intravenous resuscitation regimens for shock, management of subgroups (e.g. infants < 6 months old, infants and children with SAM who are human immunodeficiency virus sero-positive) and on the use of antibiotics.

Peginterferon alfa and ribavirin for chronic hepatitis C in patients eligible for shortened treatment, re-treatment or in HCV/HIV co-infection: a systematic review and economic evaluation.

OBJECTIVE: to assess the clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis c virus (HCV) in three specific patient subgroups affected by recent licence changes: those eligible for shortened treatment courses [i.e. those with low viral load (LVL) and who attained a rapid virological response (RVR) at 4 weeks of treatment], those eligible for re-treatment following previous non-response or relapse, and those co-infected with human immunodeficiency virus (HIV). DATA SOURCES: Fourteen electronic bibliographic databases, including the Cochrane Library, MEDLINE and EMBASE, were searched up to October 2009. Key hepatitis C resources and symposia, bibliographies of related papers and manufacturer submissions to the National Institute for Health and Clinical Excellence were also searched and clinical experts were contacted. REVIEW METHODS: A systematic review and economic evaluation were carried out. Titles and abstracts were screened for eligibility by one reviewer. Inclusion criteria were defined a priori and applied independently by two reviewers to the full text of retrieved references. For the clinical effectiveness review, studies were included if they were randomised controlled trials (RCTs) of adults with chronic HCV, restricted to the patient groups described above. The intervention was standard peginterferon and ribavirin combination therapy compared with shortened duration courses (24 weeks for genotype 1, 16 weeks for genotype 2/3) or best supportive care (BSC). Outcomes included sustained virological response (SVR), relapse rate and adverse events. In addition, full economic evaluations and studies of health-related quality of life were sought for this subgroup of patients. Data extraction and quality assessment were undertaken by two reviewers independently. Studies were synthesised through a narrative review with tabulation of results. Our previously published Markov state-transition model was adapted to estimate the cost-effectiveness of treatment strategies in subgroups of adults with chronic HCV who were eligible for shortened treatment and re-treatment and those with HCV/HIV co-infection. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs for each subgroup of patients with HCV. Categories of costs included in the model were drug acquisition, patient management, on-treatment monitoring, management of adverse events, and health-state costs for disease progression. RESULTS: In total, 2400 references were identified. Six RCTs were included in the review of clinical effectiveness, all reporting peginterferon alfa and ribavirin therapy in patients eligible for shortened treatment. In general, these RCTs were of good quality. No RCTs comparing peginterferon and ribavirin with BSC were identified for the re-treatment or co-infection populations. The results suggest that chronic HCV patients who have LVL at baseline and who achieve an RVR can be treated with shortened courses of therapy (24 weeks for genotype 1, 16 weeks for genotype 2/3) and achieve SVR rates that are comparable to those who receive the standard duration of treatment (ranges 84%-96% vs 83%-100%, respectively). However, patient numbers in the LVL/RVR subgroups were small and none of the trials was powered for this subgroup analysis, so results should be interpreted with caution. In the one trial reporting virological relapse rates in the subgroup of patients with LVL/RVR, rates were low and not statistically significantly different between those treated for 24 versus 48 weeks [3.6% vs 0%, respectively, difference 3.6%, 95% confidence interval (CI) -7.2% to 6.6%, p = 1.000]. In the cost-effectiveness analysis of shortened treatment with peginterferon alfa-2a, incremental cost-effectiveness ratios (ICERs) ranged from £35,000 to £65,000 for patients with genotype 1, whereas in patients with genotypes 2 and 3 shortened treatment dominated standard treatment. For patients with genotype 1 with LVL/RVR, shortened treatment with peginterferon alfa-2b dominated standard treatment. In patients with genotype 1 and those with genotype non-1 who were re-treated with peginterferon alfa-2a, the ICERs were £9169 and £2294, respectively. In patients with genotypes 1 and 4, who were re-treated with peginterferon alfa-2b, the ICER was £7681, whereas re-treatment dominated BSC for patients with genotypes 2 and 3. In patients co-infected with HCV/HIV, who were receiving peginterferon alfa-2a, the ICER was £7941 per quality-adjusted life-year (QALY) gained in patients with genotypes 1 and 4, whereas in patients with genotypes 2 and 3 peginterferon alfa-2a dominated BSC. In co-infected patients receiving peginterferon alfa-2b the ICER was £11,806 in genotypes 1 and 4, and £2161 in genotypes 2 and 3. CONCLUSIONS: The clinical trial evidence indicates that patients may be successfully treated with a shorter course of peginterferon combination therapy without compromising the likelihood of achieving an SVR. The economic evaluation shows that treatment with peginterferon alfa in the specified subgroups of patients with LVL/RVR will yield QALY gains, without excessive increases in costs, and may be cost saving in some situations. However, a judgement is required on the value of the QALY loss that may result from adopting a shorter treatment regimen, if shorter treatment is associated with a lower SVR than standard treatment duration. There is a need for further RCT evidence, particularly in people who have not responded to, or relapsed following, treatment. Phase II and Phase III trials are currently in progress, evaluating the safety and efficacy of protease inhibitors and nucleoside analogues for treatment-naive and treatment-experienced people with chronic HCV. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC). DATA SOURCES: Bibliographic databases were searched from 1990 to February 2009, including the Cochrane library, MEDLINE (Ovid), EMBASE (Ovid), PREMEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were assessed and experts were contacted to identify additional references and the manufacturer's submission to NICE was also searched. REVIEW METHODS: Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers using a standard form. For the clinical effectiveness review, the studies were randomised controlled trials (RCTs), which included adult participants with relapsed SCLC who responded to first-line treatment and for whom re-treatment with first-line therapy was inappropriate. The treatment was topotecan (oral or intravenous, i.v.) compared with one another, best supportive care (BSC) or other chemotherapy regimens. Outcomes included measures of response or disease progression and measures of survival. For the cost-effectiveness review studies were eligible for inclusion if they reported cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses. Data extraction and quality assessment of included studies was undertaken by one reviewer and checked by a second. Studies were synthesised through a narrative review with full tabulation of results. An independent economic model estimated the cost-effectiveness of topotecan (oral or i.v.) compared with BSC. The model used survival analysis methods to derive estimates of mean survival for patients treated with topotecan or receiving BSC alone. These were combined with quality of life (QoL) weights to derive estimates of mean quality-adjusted life expectancy for patients receiving BSC alone or topotecan plus BSC. Categories of costs included in the model included drug use, chemotherapy administration and on-treatment monitoring, management of adverse events, monitoring for disease progression and palliative care. RESULTS: A total of 434 references were identified of which five were included in the clinical effectiveness review. In these trials topotecan was compared with BSC, CAV [cyclophosphamide, Adriamycin (doxorubicin) and vincristine] or amrubicin, or oral topotecan was compared with i.v. topotecan. No economic evaluations were identified. There were no statistically significant differences between groups when i.v. topotecan was compared with either CAV or oral topotecan for overall response rate (ORR). Response rate was significantly better in participants receiving i.v. amrubicin than in those receiving a low dose of i.v. topotecan (38% versus 13%, respectively, p = 0.039). There was a statistically significant benefit in favour of oral topotecan compared with BSC (HR 0.61, 95% CI 0.43 to 0.87, p = 0.01). Drug acquisition costs for four cycles of treatment were estimated at 2550 pounds for oral topotecan and 5979 pounds for i.v. topotecan. Non-drug treatment costs accounted for an additional 1097 pounds for oral topotecan and 4289 pounds for i.v. topotecan. Total costs for the modelled time horizon of 5 years were 4854 pounds for BSC, 11,048 pounds for oral topotecan and between 16,914 pounds and 17,369 pounds for i.v. topotecan (depending on assumptions regarding time progression). Life expectancy was 0.4735, 0.7984 and 0.7784 years for BSC, oral topotecan and i.v. topotecan respectively. Total quality-adjusted life-years (QALYs) were 0.2247 and 0.4077, for BSC and oral topotecan respectively, resulting in an incremental cost-effectiveness ratio (ICER) of 33,851 pounds per QALY gained. Total QALYs for i.v. topotecan were between 0.3875 and 0.4157 (depending on assumptions regarding time progression) resulting in an ICER between 74,074 pounds and 65,507 pounds per QALY gained. CONCLUSIONS: Topotecan appeared to be better than BSC alone in terms of improved survival, and was as effective as CAV and less favourable than i.v. amrubicin in terms of response. Oral topotecan and i.v. topotecan were similar in efficacy. Topotecan offers additional benefit over BSC, but at increased cost. ICERs for i.v. topotecan, compared with BSC, were high and suggest that it is unlikely to be a cost-effective option. The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective. Further research into the QoL of patients with relapsed SCLC could identify the impacts of disease progression and treatment response.