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.

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.

'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.

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' 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.

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.

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.

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.

Mechanistic aspects of ingested chlorine dioxide on thyroid function: impact of oxidants on iodide metabolism.

Toxicological studies dealing with recent findings of health effects of drinking water disinfectants are reviewed. Experiments with monkeys and rodents indicate that the biological activity of ingested disinfectants is expressed via their chemical interaction with the mucosal epithelia, secretory products, and nutritional contents of the alimentary tract. Evidence exists that a principal partner of this redox interaction is the iodide of nutritional origin that is ubiquitous in the gastrointestinal tract. Thus the observation that subchronic exposure to chlorine dioxide (ClO2) in drinking water decreases serum thyroxine levels in mammalian species can be best explained with changes produced in the chemical form of the bioavailable iodide. Ongoing and previously reported mechanistic studies indicate that oxidizing agents such as chlorine-based disinfectants oxidize the basal iodide content of the gastrointestinal tract. The resulting reactive iodine species readily attaches to organic matter by covalent bonding. Evidence suggests that the extent to which such iodinated organics are formed is proportional to the magnitude of the electromotive force and stoichiometry of the redox couple between iodide and the disinfectant. Because the extent of thyroid uptake of the bioavailable iodide does not decrease during ClO2 ingestion, it seems that ClO2 does not cause iodide deficiency of sufficient magnitude to account for the decrease in hormonogenesis. Absorption of one or more of iodinated molecules, e.g., nutrients, hormones, or cellular constituents of the alimentary tract having thyromimetic or thyroid inhibitory properties, is a better hypothesis for the effects seen.

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.

Muscle energetics during prolonged cycling after exercise hypervolemia.

This study examined the question of whether increases in plasma volume (hypervolemia) induced through exercise affect muscle substrate utilization and muscle bioenergetics during prolonged heavy effort. Six untrained males (19-24 yr) were studied before and after 3 consecutive days of cycling (2 h/day at 65% of peak O2 consumption) performed in a cool environment (22-23 degrees C, 25-35% relative humidity). This protocol resulted in a 21.2% increase in plasma volume (P less than 0.05). During exercise no difference was found in the blood concentrations of glucose, lactate, and plasma free fatty acids at either 30, 60, 90, or 120 min of exercise before and after the hypervolemia. In contrast, blood alanine was higher (P less than 0.05) during both rest and exercise with hypervolemia. Measurement of muscle samples extracted by biopsy from the vastus lateralis muscle at rest and at 60 and 120 min of exercise indicated no effect of training on high-energy phosphate metabolism (ATP, ADP, creatine phosphate, creatine) or on selected glycolytic intermediate concentrations (glucose 1-phosphate, glucose 6-phosphate, fructose 6-phosphate, lactate). In contrast, training resulted in higher (P less than 0.05) muscle glucose and muscle glycogen concentrations. These changes were accompanied by blunting of the exercise-induced increase (P less than 0.05) in both blood epinephrine and norepinephrine concentrations. Plasma glucagon and serum insulin were not affected by the training. The results indicate that exercise-induced hypervolemia did not alter muscle energy homeostasis. The reduction in muscle glycogen utilization appears to be an early adaptive response to training mediated either by an increase in blood glucose utilization or a decrease in anaerobic glycolysis.

Transforming growth factor beta's 1, 2 and 3 inhibit proliferation of ramified microglia on an astrocyte monolayer.

The transforming growth factor beta's (TGFbeta) are a multipotent family of cytokines with strong immunosuppressive and neurotrophic effects. In the current study, we examined the effect of the TGFbeta's 1, 2 and 3 on the proliferation of ramified microglia cultured on top of a confluent astrocyte monolayer. All three TGFbeta isoforms inhibited proliferation. PCR analysis also showed the presence of mRNA for the TGFbeta receptors type I and II and for all 3 TGFbeta isoforms in microglia, astrocytes and in co-cultures. Moreover, removal of this endogenous TGFbeta activity with antibodies against TGFbeta1 and TGFbeta3 strongly stimulated microglial proliferation. These inhibitory effects on the proliferation of ramified microglia suggest that TGFbeta's may play an important role in the regulation of the microglial population under normal conditions and after injury or disease in the central nervous system.

Effects of short-term training on cardiac function during prolonged exercise.

To determine the relationship between the training-induced increases in plasma volume (PV) and alterations in cardiac performance during prolonged submaximal cycle exercise, seven male subjects were studied prior to and following a short-term (3 d) training period (2 h.d-1 at 65% VO2max). Mean (range) VO2max was 3.42 l.min-1 (2.96-3.87). Training resulted in a 20% increase (P less than 0.05) in plasma volume (PV) and a 12% increase (P less than 0.05) in total blood volume (TBV). In contrast, training had no effect (P greater than 0.05) in altering exercise VO2, VCO2, VE BTPS, or RER. Cardiac output (Q) was higher (P less than 0.05) posttraining at all exercise sampling times (30, 60, 90, and 120 min). The elevations in Q were accompanied by an average decrease (P less than 0.05) in stroke volume (SV) of 22 ml. Arteriovenous O2 (a-v O2) difference was depressed (P less than 0.05) during exercise following the training. Although elevations (P less than 0.05) in core temperature (degrees C) occurred during the exercise, the training-induced PV increases did not affect thermoregulatory behavior. These results indicate that an early adaptive response to exercise training is an elevation in Q, an increase in SV, and a reduction in HR. These effects persist during prolonged exercise in spite of the progressive increase in body heat content. It is proposed that the increase in Q serves primarily to increase muscle blood flow and maintain arterial O2 delivery, while the altered cardiodynamic behavior serves to increase cardiac reserve, providing a greater tolerance to prolonged heavy exercise.

Training-induced hypervolemia: lack of an effect on oxygen utilization during exercise.

To investigate the effect of training-induced increases in plasma volume on maximal aerobic power, 8 male subjects (age 19 to 24 yr) underwent a 4-d training program (2 h X d-1) at an estimated 71% maximal aerobic power. Following training, plasma volume measured using 131I-human serum albumin increased by 20.3% (P less than 0.01) whereas red cell volume remained unchanged and total blood volume increased by 12.3% (P less than 0.01). During progressive sub-maximal cycle exercise, oxygen consumption, carbon dioxide production, ventilation, and blood lactate concentration remained unchanged following the training whereas heart rate was significantly elevated (P less than 0.05). Significant post-training elevations were also noted in carbon dioxide production (P less than 0.05), blood lactate (P less than 0.01), and peak power output (P less than 0.05) during maximal exercise. Maximal aerobic power and ventilation were not altered. It is concluded that hypervolemia induced by short-term exercise training does not affect oxygen consumption either during sub-maximal or maximal exercise.

Autonomy and decision making between single older women and their caregiving daughters.

We examined perceptions of decisional autonomy and decision-making processes among 64 elderly, single mothers and their caregiving daughters. Mothers were highly involved in decisions affecting their lives, ranging from daily care to major health decisions; daughters were particularly influential over major health, financial and housing decisions. Mothers' level of personal care dependency was negatively associated with both mothers' and daughters' confidence in the mothers' decision-making abilities.

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.

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.

The impact of exit-site care and catheter design on the incidence of catheter-related infections.

The optimal approach to catheter exit-site care and catheter design in terms of catheter-related infections (e.g., exit-site infections, peritonitis) in children remains elusive. We retrospectively compared the incidence of exit-site infections and peritonitis in 33 pediatric peritoneal dialysis patients who used one of three exit-site care/catheter combinations. The catheters used were single-cuffed, curled Tenckhoff (T), and double-cuffed Swan neck (SN). Exit-site care included either povidone-iodine (PI) or chlorhexidine (CHL) as cleansing agents. Our data suggest that the use of chlorhexidine versus povidone-iodine is associated with a significant decrease (p < 0.05) in the frequency of catheter exit-site infections in children. The use of the Swan-neck double-cuffed catheter does not appear to have any further impact on the frequency of exit-site infections. Neither the use of chlorhexidine nor Swan neck catheters had an effect on our peritonitis rate. Our review suggests that a prospective evaluation of a chlorhexidine-based exit-site care regimen in children should be encouraged.

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.