Influence of different hormonal regimens on endometrial microvascular density and VEGF expression in women suffering from breakthrough bleeding

BACKGROUND: The aim of this study was to quantify blood vessel density (BVD) and immunoreactive vascular endothelial growth factor (VEGF) levels in endometrial biopsies taken from women suffering breakthrough bleeding (BTB) under different exogenous hormonal regimes. METHODS: Endometrial biopsies from women in Melbourne with BTB were divided into four groups: combined-continuous hormone therapy (HT) (estrogen and progestin taken daily), cyclical HT (daily estrogen with progestin for 14 days each cycle), progestin-only, or no HT. Subjects from Barcelona were using the Mirena intrauterine levonorgestrel-releasing system for contraceptive purposes, with menstrual diaries for classification into four groups (amenorrhea, infrequent, regular and prolonged). Control biopsies from Melbourne were included in the study. Endometrial samples were immunostained for VEGF and blood vessel localization using an antibody to CD34. RESULTS: Results showed that BVD was significantly reduced in the progestin-only treated group compared with the other three treatment groups (P = 0.028). In addition, all four Mirena BTB groups had significantly reduced BVD compared with controls. Considerable heterogeneity was observed in VEGF immunostaining within and between individual samples with no major differences between HT or Mirena. CONCLUSION: These results provide strong evidence that unopposed progestins reduce endometrial BVD and that there is no link between VEGF immunostaining and BVD or BTB.     

Total purchasing, community and continuing care: lessons for future policy developments in the NHS

The introduction of total purchasing pilots (TPPs) into the National Health Service (NHS) gave general practitioners (GPs) significant new opportunities to take responsibility for the development of community and continuing care (CCC) services. Based on five case studies of TPPs involved in developing CCC this paper asks three questions: (1) to what extent were the TPP’s involvement in CCC informed by an awareness of CCC policy?; (2) were TPPs involved in joint commissioning to develop integrated purchasing or provision which was informed by population based needs assessment?; (3) were TPPs seeking to involve users, carers and voluntary agencies in their plans? The findings indicate that TPPs showed little awareness of national or local policy for CCC, although their project initiatives did address some of the policy issues (in particular a recognition of the need for joint working at the practice level). At the time of fieldwork, four of the case study TPPs had begun to investigate the potential for integrated purchasing, and three of them had relatively sophisticated models of both horizontally and vertically integrated provision of care. However, the TPPs developments were not based on systematic population based needs assessment. The paper concludes that there is potential for the primary care led groups proposed in the recent white papers in England, Scotland and Wales to improve integration of care both horizontally and vertically. However, they may need policy guidance and push to: encourage them to put CCC high on their agenda for action; to work with people with expertise in population based, prevention focused, needs assessment; and to find innovative ways to include users, carers and voluntary agencies. Incentives or levers (such as control over budgets) may be needed to promote joint working between staff in different agencies.     

The diagnostic and therapeutic impact of MRI: an observational multi-centre study

AIM: To provide information about the diagnostic and therapeutic impact of magnetic resonance imaging (MRI) and to compare the findings across diagnostic groups. MATERIALS AND METHODS: A prospective, observational study of 2017 consecutive referrals for MRI of the head, spine or knee at four imaging centres. Clinicians completed questionnaires before MRI stating initial diagnoses, diagnostic confidence and treatment plans. After imaging, a second questionnaire evaluated clinicians' revised diagnosis and treatment plans in the light of imaging findings. Patients were grouped into nine diagnostic categories for analysis. Comparison between pre- and post-imaging was used to assess the diagnostic and therapeutic impact of MRI. RESULTS: In seven of nine diagnostic groups MRI findings were associated with a diagnostic impact. Diagnoses were revised or discarded following normal MR findings and diagnostic confidence was increased by confirmative MR findings. There was no statistically significant diagnostic impact for suspected pituitary or cerebello-pontine angle lesions. In five of nine diagnostic groups (knee meniscus, knee ligament, multiple sclerosis, lumbar and cervical spine) MRI findings had a clear impact on treatment plans. CONCLUSION: This study demonstrates that in most diagnostic categories, MRI influences diagnosis and treatment. However, experimental studies are needed to prove that these diagnostic and therapeutic impacts lead to improved health.Hollingworth (2000). Clinical Radiology55, 825-831.     

Ifosfamide, carboplatin, and etoposide with midcycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: clinical and quality-of-life results of the British Medical Research Council multicenter randomized LU21 trial.

PURPOSE: Ifosfamide, carboplatin, etoposide, and vincristine, alone and in combination, are highly active against small-cell lung cancer (SCLC). This trial was designed to investigate whether survival could be improved by a regimen of all four drugs (ICE-V) compared with standard chemotherapy in patients with SCLC and good performance status, and to assess the patients' quality of life (QL). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of either ICE-V at 4-week intervals without dose reduction or standard chemotherapy administered according to local practice. The recommended standard control regimens were cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide. RESULTS: A total of 402 patients were randomly assigned, and 350 (87%) patients have died. Overall survival was longer in the ICE-V group (hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = .0049), median survival was 15.6 months in the ICE-V group and 11.6 months in the control group, and 2-year survival rates were 20% and 11%, respectively. There was no evidence that the relative survival benefit for ICE-V was less in extensive-stage than in limited-stage patients. An increased rate of septicemia was reported in the ICE-V group (15% v 7% in the control group), but this did not result in an increase in reported treatment-related deaths (four patients [2%] in both groups). The findings on QL were broadly similar in both groups, with some benefit in favor of ICE-V. CONCLUSION: Compared with standard chemotherapy, the ICE-V regimen improves overall survival without QL penalties, despite an increased but manageable level of toxicity.     

The prevalence of use,dependency and harms of legal ‘party pills’ containing benzylpiperazine (BZP) and trifluorophenylmethylpiperazine (TFMPP) in New Zealand

Piperazine‐based ‘party pills’ containing 1‐benzylpiperazine (BZP) and 1‐(m‐trifluorophenylmethylphenyl)piperazine (TFMPP) have become increasingly popular in New Zealand and many other countries. The aim of this study was to collect data on the population prevalence and related harm from legal party pill use in New Zealand. A national household sample of 2010 people aged 13–45 years old was collected using a computer‐assisted telephone interviewing (CATI) facility. Twenty per cent of the sample had tried legal party pills and 15% had used them in the previous year. Approximately 40% of males aged 18–24 years old had used legal party pills in the past year. While most users reported fairly minor problems from use, such as insomnia (50% of last year users), some users reported potentially more serious physical problems, such as ‘vomiting’ (12%), ‘inability to urinate’ (10%), ‘chest pains’ (4%) and ‘seizures’ (0.8%). Users also reported a range of psychological problems from use such as visual hallucinations (9%), paranoia (8%) and depression (8%). Two per cent of last year users were classified as dependent on legal party pills using a short dependency scale. The extent of harms and incidences of more serious problems, suggest that stricter regulation of the sale and use of legal party pills in New Zealand may be appropriate.     

Stepped‐wedge cluster randomised controlled trials: a generic framework including parallel and multiple‐level designs

Stepped‐wedge cluster randomised trials (SW‐CRTs) are being used with increasing frequency in health service evaluation. Conventionally, these studies are cross‐sectional in design with equally spaced steps, with an equal number of clusters randomised at each step and data collected at each and every step. Here we introduce several variations on this design and consider implications for power. One modification we consider is the incomplete cross‐sectional SW‐CRT, where the number of clusters varies at each step or where at some steps, for example, implementation or transition periods, data are not collected. We show that the parallel CRT with staggered but balanced randomisation can be considered a special case of the incomplete SW‐CRT. As too can the parallel CRT with baseline measures. And we extend these designs to allow for multiple layers of clustering, for example, wards within a hospital. Building on results for complete designs, power and detectable difference are derived using a Wald test and obtaining the variance–covariance matrix of the treatment effect assuming a generalised linear mixed model. These variations are illustrated by several real examples. We recommend that whilst the impact of transition periods on power is likely to be small, where they are a feature of the design they should be incorporated. We also show examples in which the power of a SW‐CRT increases as the intra‐cluster correlation (ICC) increases and demonstrate that the impact of the ICC is likely to be smaller in a SW‐CRT compared with a parallel CRT, especially where there are multiple levels of clustering. Finally, through this unified framework, the efficiency of the SW‐CRT and the parallel CRT can be compared. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.     

Pulse pressure variability during hemorrhage and reinfusion in piglets: effects of age and tidal volume

Purpose

The dynamic change in arterial pulse pressure during mechanical ventilation (PPV) predicts fluid responsiveness in adults but may not be applicable to pediatric patients. We compared PPV during hemorrhage and reinfusion in immature vs mature piglets at two clinically relevant tidal volumes (V_T).

Methods

Following Institutional Animal Care Committee approval, we measured hemodynamics and PPV in two groups of piglets, 10-15 kg (immature, n = 9) and 25-30 kg (mature, n = 10), under stable intravenous anesthesia at V_T = 8 and 10 mL·kg^?1. Measurements were taken at baseline, with blood withdrawal in 5 mL·kg^?1 steps up to 30 mL·kg^?1, and during stepwise reinfusion. For each age group and V_T, we constructed receiver operating characteristic (ROC) curves to determine the threshold value that was predictive of fluid responsiveness.

Results

Pulse pressure variability was significantly lower in immature vs mature pigs and at V_T 8 vs V_T 10 at every measurement period. The difference in PPV induced by changing V_T was less in immature animals. Significant areas under the ROC curve were obtained in immature pigs at both V_Ts but in mature animals at V_T 10 alone. A PPV threshold was calculated to be 8.2% at V_T 8 and 10.9% at V_T 10 in immature animals vs 15.9% at V_T 10 in mature animals, but sensitivity and specificity were only 0.7.

Conclusion

Pulse pressure variability values are lower and less sensitive to V_T in immature vs mature pigs. Adult PPV thresholds do not apply to pediatric patients, and a single PPV value representing fluid responsiveness should not be assumed.     

Are the UK Systems of Innovation and Evaluation of Medical Devices Compatible? The Role of NICE’s Medical Technologies Evaluation Programme (MTEP)

The economic evaluation of medical products and services is increasingly prioritised by healthcare decision makers and plays a key role in informing funding allocation decisions. It is well known that there are a number of methodological difficulties in the health technology assessment of medical devices, particularly in the provision of efficacy evidence. By contrasting devices with pharmaceuticals, the way in which the differing systems of innovation mould the UK’s industry landscape is described and substantiated with market statistics. In recognition of the challenges faced by industry, as well as the growing need for cost-effective allocation of National Health Service (NHS) resources, the National Institute for Health and Care Excellence (NICE) led the development of the Medical Technologies Evaluation Programme (MTEP), which launched in 2009/2010. The review of the UK’s medical devices market supports the programme’s three principal aims: to simplify access to evaluation, speed up the process, and increase evaluative capacity for devices within NICE. However, an analysis of the output of MTEP’s first 3 years suggests that it has some way to go to meet each of these aims.     

Intravenous anti-D immunoglobulin in the treatment of resistant immune thrombocytopenic purpura in pregnancy

A 35-week pregnant 38-year-old woman presented with isolated thrombocytopenia (platelet count 4 x 10(9)/l). Investigations confirmed immune thrombocytopenic purpura, and she received treatment with prednisolone and intravenous immunoglobulins with no increment in the platelet count. At 37 and 38 weeks of the pregnancy, she received two doses of WinRho (anti-D immunoglobulin) at 50 microg/kg. Five days later, with a platelet count of 46 x 10(9)/l, she had an uncomplicated normal vaginal delivery. WinRho is a useful adjunct to other first-line treatment modalities for immune thrombocytopenia in pregnancy.