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 rollercoaster of follow-up care' after bariatric surgery: a rapid review and qualitative synthesis.

Benefits of bariatric surgery for obesity related comorbidities are well established. However, in the longer term, patients can become vulnerable to procedure specific problems, experience weight regain and continue to need monitoring and management of comorbidities. Effective longer term follow-up is vital due to these complex needs post-surgery. Current guidance recommends annual long-term follow-up after bariatric surgery. However, attendance can be low, and failure to attend is associated with poorer outcomes. Understanding patients' experiences and needs is central to the delivery of effective care. This rapid review has synthesized the current qualitative literature on patient experiences of healthcare professional (HCP) led follow-up from 12 months after bariatric surgery. A recurring theme was the need for more and extended follow-up care, particularly psychological support. Enablers to attending follow-up care were patient self-efficacy as well as HCP factors such as a non-judgemental attitude, knowledge and continuity of care. Barriers included unrealistic patient expectations and perceived lack of HCP expertise. Some preferences were expressed including patient initiated access to HCPs and more information preoperatively to prepare for potential post-surgery issues. Insights gained from this work will help identify areas for improvement to care in order to optimize longer term outcomes.

Patients' experiences of deep brain stimulation for Parkinson's disease: a qualitative systematic review and synthesis.

OBJECTIVE: To review and synthesise qualitative research studies that have explored patients' experience of deep brain stimulation (DBS) in advanced Parkinson's disease (PD). DESIGN: Systematic review and meta-synthesis of 7 original papers, using metaethnography. SETTING: Studies conducted in Denmark, France and Sweden. PARTICIPANTS: 116 patients who had undergone DBS and 9 spouses of patients. RESULTS: Prior to surgery, the experience of advancing PD is one of considerable loss and a feeling of loss of control. There are significant hopes for what DBS can bring. Following surgery, a sense of euphoria is described by many, although this does not persist and there is a need for significant transitions following this. We suggest that normality as a concept is core to the experience of DBS and that a sense of control may be a key condition for normality. Experience of DBS for patients and spouses, and of the transitions that they must undertake, is influenced by their hopes of what surgery will enable them to achieve, or regain (ie, a new normality). CONCLUSIONS: There is a need for further qualitative research to understand the nature of these transitions to inform how best patients and their spouses can be supported by healthcare professionals before, during and after DBS. In assessing the outcomes of DBS and other treatments in advanced PD, we should consider how to capture holistic concepts such as normality and control. Studies that examine the outcomes of DBS require longer term follow-up.

The use of qualitative methods to inform Delphi surveys in core outcome set development.

BACKGROUND: Core outcome sets (COS) help to minimise bias in trials and facilitate evidence synthesis. Delphi surveys are increasingly being used as part of a wider process to reach consensus about what outcomes should be included in a COS. Qualitative research can be used to inform the development of Delphi surveys. This is an advance in the field of COS development and one which is potentially valuable; however, little guidance exists for COS developers on how best to use qualitative methods and what the challenges are. This paper aims to provide early guidance on the potential role and contribution of qualitative research in this area. We hope the ideas we present will be challenged, critiqued and built upon by others exploring the role of qualitative research in COS development. This paper draws upon the experiences of using qualitative methods in the pre-Delphi stage of the development of three different COS. Using these studies as examples, we identify some of the ways that qualitative research might contribute to COS development, the challenges in using such methods and areas where future research is required. RESULTS: Qualitative research can help to identify what outcomes are important to stakeholders; facilitate understanding of why some outcomes may be more important than others, determine the scope of outcomes; identify appropriate language for use in the Delphi survey and inform comparisons between stakeholder data and other sources, such as systematic reviews. Developers need to consider a number of methodological points when using qualitative research: specifically, which stakeholders to involve, how to sample participants, which data collection methods are most appropriate, how to consider outcomes with stakeholders and how to analyse these data. A number of areas for future research are identified. CONCLUSIONS: Qualitative research has the potential to increase the research community's confidence in COS, although this will be dependent upon using rigorous and appropriate methodology. We have begun to identify some issues for COS developers to consider in using qualitative methods to inform the development of Delphi surveys in this article.

Patients' attitudes to risk in lung cancer surgery: A qualitative study.

OBJECTIVES: Lung cancer surgery leads to long term survival for some patients but little is known about how patients decide whether to accept the associated surgical risks. The objective of this qualitative study was to explore patients' attitudes to the risks associated with lung cancer surgery. METHODS: Fifteen patients with resectable lung cancer, recruited via multi-disciplinary team meetings at an English tertiary referral centre, participated in semi-structured interviews to explore their attitudes to the morbidity and mortality risks associated with lung cancer surgery. Transcripts were analysed using the framework method. RESULTS: Participants reported being 'pleased' to hear that they were suitable for surgery and felt that surgery was not a treatment to be turned down because they did not see any alternatives. Participants had some knowledge of perioperative risks, including mortality estimates; however, many voiced a preference not to know these risks and to let the medical team decide their treatment plan. Some found it difficult to relate the potential risks and complications of surgery to their own situation and appeared willing to accept high perioperative mortality risks. Generally, participants were willing to accept quite severe long-term postoperative breathlessness; however, it was apparent that many actually found this possibility difficult to imagine. CONCLUSION: Patients do not necessarily wish to know details of risks associated with lung cancer surgery and may wish to defer decisions about treatment to their medical team. Investment in the doctor-patient relationship, particularly for the surgeon, is therefore important in the management of patients with lung cancer.

Neural dysfunction in ADHD with Reading Disability during a word rhyming Continuous Performance Task.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous, neurodevelopmental disorder which co-occurs often with Reading Disability (RD). ADHD with and without RD consistently have higher inattentive ratings compared with typically developing controls, with co-occurring ADHD and RD also demonstrating impaired phonological processing. Accordingly, inattention has been associated with greater phonological impairment, though the neural correlates of the association are poorly understood from a functional neuroimaging perspective. It was postulated that only the co-occurring subgroup would demonstrate hypoactivation of posterior, left hemispheric, reading-related areas and, to a lesser extent, alterations in right hemispheric, attention areas compared with controls. METHODS: A novel word rhyming Continuous Performance Task assesses functional activation differences in phonology- and attention-related areas between three groups: ten boys with ADHD and RD, fourteen boys with ADHD without RD, and fourteen typically developing controls. Subjects respond to words that rhyme with a target word as mono- and disyllabic, English words are visually presented over 90s blocks. RESULTS: Behavioral performance was not different between groups. Some hypoactivation of left hemispheric, reading-related areas was apparent in ADHD and RD, but not ADHD without RD, compared with controls. Right hemispheric, attention areas showed alterations in both ADHD subgroups relative to controls; however, the differences for each subgroup were dissimilar. CONCLUSIONS: The dorsal decoding subnetwork may not be grossly compromised in ADHD with Reading Disability. The role of cognitive impairments, including the level of inattention, on phonology requires clarification from a neuroimaging perspective.

How well do waist circumference and body mass index reflect body composition in pre-pubertal children?

OBJECTIVE: To investigate the quantitative relationship between waist circumference (WC) and height (Ht), and subsequently the association between waist circumference index (WCI), body mass index (BMI) and body composition in pre-pubertal children. DESIGN: Cross-sectional sample (n=227; boys=127) of pre-pubertal black children (age range 8.8-11.0 years) from the Bone Health sub-study of the Bt20 birth cohort study set in Soweto-Johannesburg, South Africa. Measures of height, weight and WC by anthropometry, total and truncal fat and lean mass by dual-energy X-ray absorptiometry were used in the analysis. Pearson's correlation coefficients were used to examine the associations between BMI, WC and body composition outcomes. RESULTS: WC was independent of height when height was raised to a power of approximately 0.8. BMI and WCI (WC/Ht) were significantly associated with total and truncal fat and lean mass in both sexes (all P<0.001). BMI showed consistently and significantly higher correlations with body composition than WCI and this association was significantly greater for fat mass than lean mass. CONCLUSION: BMI, rather than WCI, would be a better screening tool for total and truncal fat mass in both sexes before puberty.

BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury.

Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery.

Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury.

Neural stem cells (NSCs) offer the potential to replace lost tissue after nervous system injury. This study investigated whether grafts of NSCs (mouse clone C17.2) could also specifically support host axonal regeneration after spinal cord injury and sought to identify mechanisms underlying such growth. In vitro, prior to grafting, C17.2 NSCs were found for the first time to naturally constitutively secrete significant quantities of several neurotrophic factors by specific ELISA, including nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. When grafted to cystic dorsal column lesions in the cervical spinal cord of adult rats, C17.2 NSCs supported extensive growth of host axons of known sensitivity to these growth factors when examined 2 weeks later. Quantitative real-time RT-PCR confirmed that grafted stem cells expressed neurotrophic factor genes in vivo. In addition, NSCs were genetically modified to produce neurotrophin-3, which significantly expanded NSC effects on host axons. Notably, overexpression of one growth factor had a reciprocal effect on expression of another factor. Thus, stem cells can promote host neural repair in part by secreting growth factors, and their regeneration-promoting activities can be modified by gene delivery.

Interleukin-6 (IL6) and cellular response to facial nerve injury: effects on lymphocyte recruitment, early microglial activation and axonal outgrowth in IL6-deficient mice.

Nerve injury triggers numerous changes in the injured neurons and surrounding non-neuronal cells. Of particular interest are molecular signals that play a role in the overall orchestration of this multifaceted cellular response. Here we investigated the function of interleukin-6 (IL6), a multifunctional neurotrophin and cytokine rapidly expressed in the injured nervous system, using the facial axotomy model in IL6-deficient mice and wild-type controls. Transgenic deletion of IL6 caused a massive decrease in the recruitment of CD3-positive T-lymphocytes and early microglial activation during the first 4 days after injury in the axotomized facial nucleus. This was accompanied by a more moderate reduction in peripheral regeneration at day 4, lymphocyte recruitment (day 14) and enhanced perikaryal sprouting (day 14). Motoneuron cell death, phagocytosis by microglial cells and recruitment of granulocytes and macrophages into injured peripheral nerve were not affected. In summary, IL6 lead to a variety of effects on the cellular response to neural trauma. However, the particularly strong actions on lymphocytes and microglia suggest that this cytokine plays a central role in the initiation of immune surveillance in the injured central nervous system.

Chronic intrathecal infusions after spinal cord injury cause scarring and compression.

Intrathecal infusions are used in a number of rodent studies to deliver substances to the injured spinal cord. Whereas this method has been successful in certain paradigms, two potential limitations of this model have not been extensively reported: (1) scar formation at the catheter tip, which can lead to infusion failure, and (2) damage to the spinal cord caused by the catheter itself. Thus, the purpose of the present study was threefold: (1) to determine intrathecal infusion efficiency over 14 days following spinal cord injury; (2) to examine possible secondary damage caused by intrathecal tubing; and (3) to explore whether alternative protocols that avoid such damage are effective. Adult Fischer 344 rats were subjected to spinal cord lesions at T7, followed by placement of an intrathecal catheter attached to an Alzet minipump. Seven or 14 days following injury and catheter placement, tube patency was evaluated by diffusion of Evans Blue dye from the minipump. Results indicate that infusion was efficient 7 days following injury but was markedly reduced after 14 days. Further, histology and immunocytochemistry 14 days after injury demonstrated compression damage to the cord where the tubing rested. Alternative protocols, including intrathecal infusions through metal cannulae, or "drip" infusions directly over the lesion, did not improve delivery. These data suggest that results from rodent studies using infusion from catheters placed adjacent to lesion sites may be attributable to acute or subacute effects of the delivered substance. Future rodent studies using intrathecal infusions should include rigorous evaluation of infusion efficiency and possible secondary tissue damage.

Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury.

Injury to the adult mammalian spinal cord results in extensive axonal degeneration, variable amounts of neuronal loss, and often severe functional deficits. Restoration of controlled function depends on regeneration of these axons through an injury site and the formation of functional synaptic connections. One strategy that has emerged for promoting axonal regeneration after spinal cord injury is the implantation of autologous Schwann cells into sites of spinal cord injury to support and guide axonal growth. Further, more recent experiments have shown that neurotrophic factors can also promote axonal growth, and, when combined with Schwann cell grafts, can further amplify axonal extension after injury. Continued preclinical development of these approaches to neural repair may ultimately generate strategies that could be tested in human injury.

Influence of life-history parameters on organochlorine concentrations in free-ranging killer whales (Orcinus orca) from Prince William Sound, AK.

Certain populations of killer whales (Orcinus orca) have been extensively studied over the past 30 years, including populations that use Puget Sound, WA, the inside waters of British Columbia, Southeastern Alaska and Kenai Fjords/Prince William Sound, Alaska. Two eco-types of killer whales, 'transient' and 'resident', occur in all of these regions. These eco-types are genetically distinct and differ in various aspects of morphology, vocalization patterns, diet and habitat use. Various genetic and photo-identification studies of eastern North Pacific killer whales have provided information on the male-female composition of most of these resident pods and transient groups, as well as the approximate ages, reproductive status and putative recruitment order (birth order) of the individual whales. Biopsy blubber samples of free-ranging resident and transient killer whales from the Kenai Fjords/Prince William Sound, AK region were acquired during the 1994-1999 field seasons and analyzed for selected organochlorines (OCs), including dioxin-like CB congeners and DDTs. Concentrations of OCs in transient killer whales (marine mammal-eating) were much higher than those found in resident animals (fish-eating) apparently due to differences in diets of these two killer whale eco-types. Certain life-history parameters such as sex, age and reproductive status also influenced the concentrations of OCs in the Alaskan killer whales. Reproductive female whales contained much lower levels of OCs than sexually immature whales or mature male animals in the same age class likely due to transfer of OCs from the female to her offspring during gestation and lactation. Recruitment order also influenced the concentrations of OCs in the Alaskan killer whales. In adult male residents, first-recruited whales contained much higher OC concentrations than those measured in non-first-recruited (e.g. second recruited, third recruited) resident animals in the same age group. This study provides baseline OC data for free ranging Alaskan killer whales for which there is little contaminant information.

Chest wall peritoneal dialysis catheter placement in infants with a colostomy.

The presence of a colostomy in infants with end-stage renal disease (ESRD) receiving peritoneal dialysis (PD) is associated with an inherent risk for contamination and the development of a PD catheter-associated infection. A two-piece presternal catheter designed to reduce the incidence of such infections has been used in a small number of children, but the implantation of the catheter is technically difficult, and there is a risk of disconnection of the two parts secondary to rapid patient growth in the first year of life. Alternatively, a conventional Swan neck catheter, larger than typically required, can be placed with its exit site located on the chest wall. Over the past three years, we adopted this novel approach in two patients with ESRD and a colostomy in whom PD catheters were placed at ages 4 days and 12 days, respectively. During a combined follow-up of 50 months, only one episode of peritonitis and no episodes of exit-site or tunnel infection have been observed. This experience supports the use of this unique approach to PD catheter placement in infants with ESRD and a colostomy.

Regulation of the cell adhesion molecule CD44 after nerve transection and direct trauma to the mouse brain.

CD44 is a cell surface glycoprotein involved in cell adhesion during neurite outgrowth, leukocyte homing, and tumor metastasis. In the current study, we examined the regulation of this molecule 4 days after neural trauma in different forms of central and peripheral injury. Transection of the hypoglossal, vagus, or sciatic nerve led to the appearance of CD44-immunoreactivity (CD44-IR) on the surface of the affected motoneurons, their dendrites, and their axons. Fimbria fornix transection led to CD44-IR on a subpopulation of cholinergic neurons in the ipsi- and contralateral medial septum and diagonal band of Broca and colocalized with galanin-IR. Central projections of axotomized sensory neurons to the spinal cord (substantia gelatinosa, Clarke's column) also showed an increase in CD44-IR, which was abolished by spinal root transection. Nonneuronal CD44-IR was mainly restricted to sites of direct injury. In the crushed sciatic nerve, CD44-IR was found on the demyelinating Schwann cells and on infiltrating monocytes and granulocytes. Direct parasagittal transection of the cerebral cortex led to CD44-IR on resident astrocytes and on leukocytes entering the injured forebrain tissue. CD44-IR also increased on reactive retinal astrocytes and microglia after the optic nerve crush. Additional time points in the retina and hypoglossal nucleus (days 1, 2, and 14) and cerebral cortex (day 2) injury models also showed the same cell type pattern for the CD44-IR. Finally, polymerase chain reaction analysis confirmed the posttraumatic expression of CD44 mRNA and detected only the standard haematopoietic CD44 splice isoform both in direct and indirect brain injury models. Overall, the current study shows the widespread, graded appearance of CD44-IR on neurons and on nonneuronal cells, depending on the form of neural injury. Here, the ability of CD44 to bind to a variety of extracellular matrix and cell adhesion proteins and its common presence in different forms of brain pathology could suggest an important role for this cell surface glycoprotein in the neuronal, glial, and leukocyte response to trauma and in the repair of the damaged nervous system.

Impaired axonal regeneration in alpha7 integrin-deficient mice.

The interplay between growing axons and the extracellular substrate is pivotal for directing axonal outgrowth during development and regeneration. Here we show an important role for the neuronal cell adhesion molecule alpha7beta1 integrin during peripheral nerve regeneration. Axotomy led to a strong increase of this integrin on regenerating motor and sensory neurons, but not on the normally nonregenerating CNS neurons. alpha7 and beta1 subunits were present on the axons and their growth cones in the regenerating facial nerve. Transgenic deletion of the alpha7 subunit caused a significant reduction of axonal elongation. The associated delay in the reinnervation of the whiskerpad, a peripheral target of the facial motor neurons, points to an important role for this integrin in the successful execution of axonal regeneration.

Molecular signals for glial activation: pro- and anti-inflammatory cytokines in the injured brain.

Injury to the central nervous system leads to cellular changes not only in the affected neurons but also in adjacent glial cells. This neuroglial activation is a consistent feature in almost all forms of brain pathology and appears to reflect an evolutionarily-conserved program which plays an important role for the repair of the injured nervous system. Recent work in mice that are genetically-deficient for different cytokines (M-CSF, IL-6, TNF-alpha, TGF-beta 1) has begun to shed light on the molecular signals that regulate this cellular response. Here, the availability of cytokine-deficient animals with reduced or abolished neuroglial activation provides a direct approach to determine the function of the different components of the cellular response leading to repair and regeneration following neural trauma.

Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function.

Damage to the central nervous system (CNS) leads to cellular changes not only in the affected neurons but also in adjacent glial cells and endothelia, and frequently, to a recruitment of cells of the immune system. These cellular changes form a graded response which is a consistent feature in almost all forms of brain pathology. It appears to reflect an evolutionarily conserved program which plays an important role in the protection against infectious pathogens and the repair of the injured nervous system. Moreover, recent work in mice that are genetically deficient for different cytokines (MCSF, IL1, IL6, TNFalpha, TGFbeta1) has begun to shed light on the molecular signals that regulate this cellular response. Here we will review this work and the insights it provides about the biological function of the neuroglial activation in the injured brain.

Symptoms of patients with myasthenia gravis receiving treatment.

The symptoms of myasthenia gravis (MG) are often simply classified as excessive fatigue rather than evaluated as different signs of disease progression. The purpose of this study was to evaluate the medical symptoms of patients with MG who had been under treatment for many years. Patients diagnosed with MG were compared to healthy controls. A survey questionnaire was used and differences were evaluated using non-parametric statistics. Health care givers should be aware of these differences in order to facilitate early appropriate treatment, to decrease disability, and to increase the quality of life.