Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

Rapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Nanoscale adhesion profiling and membrane characterisation in sickle cell disease using hybrid atomic force microscopy-IR spectroscopy.

Sickle cell disease (SCD) presents a significant global health problem. At present there is no effective treatment, with most being supportive for its associated complications such as the vaso-occlusive crises that result from increased cell adhesion. Hypoxic sickle cells have previously shown greater phosphatidylserine (PS) exposure and oxidative damage, as well as being notably "stickier" suggesting that increased cell cohesion and adhesion to the blood vessel endothelium is a possible mechanism for vaso-occlusion. The present work uses the hybrid technique of atomic force microscopy nano-infrared spectroscopy (AFM-IR) to probe changes to the coefficient of friction and C-O IR intensity in SCD on a nanoscale for dried red blood cells (RBCs) fixed under conditions of hypoxia and correlates these observations with adhesive interactions at the membrane. Using functionalised AFM tips, it has been possible to probe adhesive interactions between hydrophilic and hydrophobic moieties exposed at the surface of the dried RBCs fixed under different oxygenation states and for different cell genotypes. The results are consistent with greater PS-exposure and oxidative damage in hypoxic sickle cells, as previously proposed, and also show strong correlation between localised oxidative damage and increased adhesion. A mechanistic explanation involving significant lipid tail disruption as a result of oxidative action, in combination with differing concentrations of externalised PS lipids, is proposed to explain the observed adhesion behaviour of each type of cell.

Yoda1 and phosphatidylserine exposure in red cells from patients with sickle cell anaemia.

Phosphatidylserine (PS) exposure is increased in red cells from sickle cell anaemia (SCA) patients. Externalised PS is prothrombotic and attractive to phagocytes and activated endothelial cells and thus contributes to the anaemic and ischaemic complications of SCA. The mechanism of PS exposure remains uncertain but it can follow increased intracellular Ca2+ concentration ([Ca2+]i). Normally, [Ca2+]i is maintained at very low levels but in sickle cells, Ca2+ permeability is increased, especially following deoxygenation and sickling, mediated by a pathway sometimes called Psickle. The molecular identity of Psickle is also unclear but recent work has implicated the mechanosensitive channel, PIEZO1. We used Yoda1, an PIEZO1 agonist, to investigate its role in sickle cells. Yoda1 caused an increase in [Ca2+]i and PS exposure, which was inhibited by its antagonist Dooku1 and the PIEZO1 inhibitor GsMTx4, consistent with functional PIEZO1. However, PS exposure did not necessitate an increase in [Ca2+]i. Two PKC inhibitors were also tested, chelerytherine chloride and calphostin C. Both reduced PS exposure whilst chelerytherine chloride also reduced Yoda1-induced increases in [Ca2+]i. Findings are therefore consistent with the presence of PIEZO1 in sickle cells, able to mediate Ca2+ entry but that PKC was also involved in both Ca2+ entry and PS exposure.

Supracondylar periprosthetic femoral fractures following total knee arthroplasty: treatment with a retrograde intramedullary nail.

Total knee replacement surgery is occasionally complicated by a supracondylar periprosthetic fracture, and this presents a challenging problem in an often frail population. Multiple nonoperative and operative treatments have been described which have the aim of restoring the patient to their pre-injury status. This study retrospectively reviews the results of the largest series to date of 14 such fractures treated by retrograde intramedullary supracondylar nailing and is supportive of its continued use with good functional outcomes, low complication rates, and 100% fracture union.

Clinical experience with the long-acting injectable formulation of the atypical antipsychotic, risperidone.

BACKGROUND: To detail specific effects of long-acting risperidone on individuals with schizophrenia and their way of life in a series of four cases. METHOD: Four patients with schizophrenia were selected from four different psychiatric centres. Patients were established on an oral dose of risperidone (1-4 mg/day) for 2 weeks. Based on their oral dose, they then received intramuscular injections of 25 mg or 50 mg of long-acting risperidone every 2 weeks, which could be adjusted according to clinical response. Assessments of efficacy (Positive And Negative Syndrome Scale, Clinical Global Impression-Severity) and safety (Extrapyramidal Symptom Rating Scale) were made at intervals throughout a 1-year period. RESULTS: Patients demonstrated a variety of reasons for receiving a long-acting injectable antipsychotic drug, including insufficient control of symptoms, adverse events and convenience. After 1 year of treatment with long-acting risperidone, all patients showed improvements in their symptoms of schizophrenia over their original stable condition, and benefited from a considerable reduction or total disappearance of pre-existing extrapyramidal symptoms. Patients were more socially interactive, with no signs of sedation, fatigue, confusion, depression or anxiety, and none were considered to have relapsed or to require hospitalisation. Three of the four patients were considered to have had no signs of illness after 1 year, one of whom had returned to college and another to work. They demonstrate that patients can be switched from oral and depot medications without problems. There was little pain or discomfort and no inflammatory response experienced at the injection site. CONCLUSION: The cases demonstrate the suitability of long-acting risperidone in patients benefiting from long-term treatment and suggest its potential in all patients who are at risk of relapse.

Is the incidence of psychotic disorder in decline? Epidemiological evidence from two decades of research.

BACKGROUND: It is unclear whether the incidence of first episode psychoses is in decline. We had the opportunity to determine whether incidence had changed over a 20-year period in a single setting, and test whether this could be explained by demographic or clinical changes. METHODS: The entire population at-risk aged 16-54 in Nottingham over three time periods (1978-80, 1993-95 and 1997-99) were followed up. All participants presenting with an ICD-9/10 first episode psychosis were included. The remainder of the population at-risk formed the denominator. Standardized incidence rates were calculated at each time period with possible change over time assessed via Poisson regression. We studied six outcomes: substance-induced psychoses, schizophrenia, other non-affective psychoses, manic psychoses, depressive psychoses and all psychotic disorders combined. RESULTS: Three hundred and forty-seven participants with a first episode psychosis during 1.2 million person-years of follow-up over three time periods were identified. The incidence of non-affective or affective psychoses had not changed over time following standardization for age, sex and ethnicity. We observed a linear increase in the incidence of substance-induced psychosis, per annum, over time (incidence rate ratios: 1.15; 95% CI 1.05-1.25). This could not be explained by longitudinal changes in the age, sex and ethnic structure of the population at-risk. CONCLUSIONS: Our findings suggest psychotic disorders are not in decline, though there has been a change in the syndromal presentation of non-affective disorders, away from schizophrenia towards other non-affective psychoses. The incidence of substance-induced psychosis has increased, consistent with increases in substance toxicity over time, rather than changes in the prevalence or vulnerability to substance misuse. Increased clinical and popular awareness of substance misuse could also not be excluded.

Prevalence of substance misuse in first-episode psychosis.

BACKGROUND: Reports suggest a high prevalence of substance misuse in psychotic disorders but few studies examine comorbidity at onset of psychosis. AIMS: To identify the prevalence and pattern of substance use and misuse in first-episode psychosis, and relationships with diagnosis, mode of presentation and demographic variables. METHOD: Consensus diagnoses for 168 subjects presenting with first-episode psychosis were made using ICD-10 diagnostic criteria. Information on substance use and misuse was obtained from multiple sources. We examined associations between substance misuse, diagnosis and demographic factors. RESULTS: Criteria for drug use, drug misuse or alcohol misuse were met by 37% of the sample. One-year prevalence rates were 19.5% (drug misuse) and 11.7% (alcohol misuse). Thirteen subjects (8.4%) received a primary diagnosis of substance-related psychotic disorder; a significant increase compared with an earlier cohort from the same catchment area. Drug misuse was associated with younger age of onset of psychosis, male gender and non-African-Caribbean ethnicity. CONCLUSIONS: This study confirms high rates of substance misuse at onset of psychosis. There is evidence for an increase in diagnosis of substance-related psychotic disorders over time. Those most at risk of substance misuse are young males.

Diagnostic stability of first-episode psychosis. Comparison of ICD-10 and DSM-III-R systems.

BACKGROUND: The temporal stability of a diagnosis is one measure of its predictive validity. AIMS: To measure diagnostic stability in first-episode psychosis using ICD-10 and DSM-III-R. METHOD: Between 1992 and 1994 we ascertained a cohort of persons with first-episode psychosis (n = 168), assigning to each a consensus diagnosis. At three-year follow-up, longitudinal consensus diagnoses, blind to onset diagnoses, were made. Stability was measured by the positive predictive values (PPVs) of onset diagnoses. For onset schizophrenia, we also calculated sensitivity, specificity and concordance (kappa). RESULTS: First-episode ICD-10 and DSM-III-R schizophrenia had a PPV of over 80% at three years. Over one-third of cases with ICD-10 F20 schizophrenia at three years had non-schizophrenia diagnoses at onset. Manic psychoses showed the highest PPV (91%). For onset schizophrenia, both systems had high specificity (ICD-10: 89; DSM-III-R: 93%), but low sensitivity (ICD-10: 64%; DSM-III-R: 51%) and moderate concordance (ICD-10: 0.54; DSM-III-R: 0.46). CONCLUSIONS: Bipolar disorders and schizophrenia showed the highest stability. DSM-III-R schizophrenia did not have greater stability than ICD-10 schizophrenia.

Aggressive incidents in first-episode psychosis.

BACKGROUND: Recent research has reported increased risk of aggressive incidents by individuals with psychotic illness. AIMS: To examine acts of aggression in first-episode psychosis. METHOD: Subjects with a first-episode psychosis were ascertained from a defined catchment area (Nottingham, UK) and reassessed at 3 years (n=166) using clinical interview, informants, health care and forensic records. RESULTS: Of the subjects, 9.6% demonstrated at least one act of serious aggression (defined as weapon use, sexual assault or victim injury) during at least one psychotic episode and 23.5% demonstrated lesser acts of aggression (defined as all other acts of aggression). For all aggressive subjects (33.1%), unemployment (OR=3.6, 95% C11.6-8.0), comorbid substance misuse (OR=3.1, C1 1.1-8.8) and symptoms of overactivity at service contact (OR=6.9,C1 2.7-17.8) had independent effects on risk of aggression. CONCLUSIONS: We confirmed some previously reported demographic and clinical associations with aggression in first-episode psychosis but no relationship with specific psychotic symptoms or diagnostic groups was observed.

Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom.

BACKGROUND: Several studies have replicated the finding of increased incidence of schizophrenia and related psychoses in first and second generation migrants from the Caribbean. The finding has remained consistent in studies employing different methods, but concern has been expressed about indirect methods of calculating the population at risk. This study aims to overcome these short-comings. METHOD: A further prospective study was undertaken in Nottingham assembling an inception cohort of psychotic patients (N = 168) presenting from a defined catchment area. The 1991 census, which includes codings for self-ascribed ethnic origin, was used to calculate the denominator, employing correction factors for potential under-enumeration. Case-ascertainment was based upon all service contacts and subjects had in-depth assessments including the SCAN. Collateral history was obtained from informants. RESULTS: Subjects born in the Caribbean, or who had one or both parents born in the Caribbean, had a greatly elevated risk (incidence ratios above 7) for all psychotic disorders and for ICD-10 (DCR)-defined F20 Schizophrenia. CONCLUSIONS: The size of the increase and the methodological safeguards employed support the validity of this now highly replicated finding. A personal or family history of migration from the Caribbean is a major risk factor for psychosis; the consistency of this finding justifies a systematic evaluation of potential aetiological factors. Any hypothesis derived from the evidence so far must explain: increased incidence in first and second generation migrants; increased risk for all psychoses (including affective psychoses); and an effect specifically associated with a migration history from the Caribbean to Northern Europe.

Incidence of schizophrenia in Nottingham. A comparison of two cohorts, 1978-80 and 1992-94.

BACKGROUND: Several studies have reported a decline of up to 50% in the incidence of schizophrenia over recent decades. We aimed to measure changes in the incidence and diagnostic patterns of first-episode psychosis by comparing two Nottingham cohorts, identified in two equal periods separated by 14 years. METHOD: Two prospectively ascertained cohorts of first-episode psychotic disorder were identified over the time periods 1978-80 and 1992-94. The earlier cohort was of the World Health Organization Determinants of Outcome of Severe Mental Disorder (DOSMD) ten-country study. The later cohort was obtained using similar methodology. Both groups were diagnosed using ICD-10 diagnostic criteria and age-standardised incidence rates were compared. RESULTS: The standardised incidence rate for all psychotic disorders rose slightly from 2.49 to 2.87 per 10000 population per year, but the F20 classification fell significantly by over a third (1.41 to 0.87 per 10000 per year). The second study group (1992-1994) included a greater diversity of psychotic diagnoses compared with the first, in particular an increased proportion of acute and drug-related psychoses. CONCLUSIONS: Methodological considerations call for caution in interpreting such data, but we conclude that the significant fall in the narrowly defined diagnostic category of schizophrenia reflects a real change in the syndromal presentation of psychotic disorders.