Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

BACKGROUND: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. METHODS: We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. RESULTS: Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. CONCLUSION: We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

Whole-Genome Sequencing Has the Potential To Improve Treatment for Rifampicin-Resistant Tuberculosis in High-Burden Settings: a Retrospective Cohort Study.

Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardized and based on limited drug susceptibility testing (DST). More individualized treatment with expanded DST access is likely to improve patient outcomes. To assess the potential of TB drug resistance prediction based on whole-genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorize patients into a recommended regimen, either a standardized short regimen or a longer individualized regimen. Potential regimen changes were then described with the addition of WGS-derived DST. WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008 to 2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) patients may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualized regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualization. These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.

"This is not my body": Therapeutic experiences and post-treatment health of people with rifampicin-resistant tuberculosis.

BACKGROUND: There are few data on the on post-treatment experiences of people who have been successfully treated for rifampicin-resistant (RR-)TB. OBJECTIVE: To describe the experiences and impact of RR-TB disease and therapy on post-treatment life of individuals who were successfully treated. METHODS: In this qualitative study in-depth interviews were conducted among a purposively selected sample from a population of individuals who were successfully treated for RR-TB between January 2008 and December 2018. Interview transcripts and notes were analysed using a thematic network analysis which included grounded theory and a framework for understanding pathophysiological mechanisms for post-TB morbidity and mortality. The analysis was iterative and the coding system developed focused on disease, treatment and post-treatment experiences of individuals. This paper follows the COREQ guidelines. RESULTS: For all 12 participants interviewed, the development of RR-TB disease, its diagnosis and the subsequent treatment were a major disruption to their lives as well as a transformative experience. On diagnosis of RR-TB disease, participants entered a liminal period in which their lives were marked with uncertainty and dominated by physical and mental suffering. Irrespective of how long ago they had completed their treatment, they all remembered with clarity the signs and symptoms of the disease and the arduous treatment journey. Post-treatment participants reported physical, social, psychological and economic changes as consequences of their RR-TB disease and treatment. Many participants reported a diminished ability to perform physical activities and, once discharged from the RR-TB hospital, inadequate physical rehabilitation. For some, these physical limitations impacted on their social life, and ultimately on their psychological health as well as on their ability to earn money and support their families. CONCLUSION: The experiences and impact of RR-TB disease and therapy on post-treatment life of individuals successfully treated, highlights gaps in the current health care system that need to be addressed to improve the life of individuals post-treatment. A more holistic and long-term view of post-TB health, including the provision of comprehensive medical and social services for post-treatment care of physical ailments, social re-integration and the mitigation of the perceived fear and risk of getting TB again could be a central part of person-centred TB care.

Group 5 drugs for multidrug-resistant tuberculosis: individual patient data meta-analysis.

The role of so-called "group 5" second-line drugs as a part of antibiotic therapy for multidrug-resistant tuberculosis (MDR-TB) is widely debated. We performed an individual patient data meta-analysis to evaluate the effectiveness of several group 5 drugs including amoxicillin/clavulanic acid, thioacetazone, the macrolide antibiotics, linezolid, clofazimine and terizidone for treatment of patients with MDR-TB.Detailed individual patient data were obtained from 31 published cohort studies of MDR-TB therapy. Pooled treatment outcomes for each group 5 drug were calculated using a random effects meta-analysis. Primary analyses compared treatment success to a combined outcome of failure, relapse or death.Among 9282 included patients, 2191 received at least one group 5 drug. We found no improvement in treatment success among patients taking clofazimine, amoxicillin/clavulanic acid or macrolide antibiotics, despite applying a number of statistical approaches to control confounding. Thioacetazone was associated with increased treatment success (OR 2.6, 95% CI 1.1-6.1) when matched controls were selected from studies in which the group 5 drugs were not used at all, although this result was heavily influenced by a single study.The development of more effective antibiotics to treat drug-resistant TB remains an urgent priority.

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial.

BACKGROUND: Acupuncture is used by patients as a treatment for irritable bowel syndrome (IBS) but the evidence on effectiveness is limited. The purpose of the study was to evaluate the effectiveness of acupuncture for irritable bowel syndrome in primary care when provided as an adjunct to usual care. DESIGN: A two-arm pragmatic randomised controlled trial. SETTING: Primary care in the United Kingdom. PATIENTS: 233 patients had irritable bowel syndrome with average duration of 13 years and score of at least 100 on the IBS Symptom Severity Score (SSS). INTERVENTIONS: 116 patients were offered 10 weekly individualised acupuncture sessions plus usual care, 117 patients continued with usual care alone. MEASUREMENTS: Primary outcome was the IBS SSS at three months, with outcome data collected every three months to 12 months. RESULTS: There was a statistically significant difference between groups at three months favouring acupuncture with a reduction in IBS Symptom Severity Score of -27.43 (95% CI: -48.66 to -6.21, p=0.012). The number needed to treat for successful treatment (≥50 point reduction in the IBS SSS) was six (95% CI: 3 to 17), based on 49% success in the acupuncture group vs. 31% in the control group, a difference between groups of 18% (95% CI: 6% to 31%). This benefit largely persisted at 6, 9 and 12 months. CONCLUSIONS: Acupuncture for irritable bowel syndrome provided an additional benefit over usual care alone. The magnitude of the effect was sustained over the longer term. Acupuncture should be considered as a treatment option to be offered in primary care alongside other evidenced based treatments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

A pragmatic multicentered randomized controlled trial of yoga for chronic low back pain: economic evaluation.

STUDY DESIGN: Multicentered randomized controlled trial with quality of life and resource use data collected. OBJECTIVE: The objective of this study was to evaluate the cost-effectiveness of yoga intervention plus usual care compared with usual care alone for chronic or recurrent low back pain. SUMMARY OF BACKGROUND DATA: Yoga has been shown as an effective intervention for treating chronic or recurrent low back pain. However, there is little evidence on its cost-effectiveness. The data are extracted from a pragmatic, multicentered, randomized controlled trial that has been conducted to evaluate the effectiveness and cost-effectiveness of a 12-week progressive program of yoga plus usual care in patients with chronic or recurrent low back pain. METHODS: With this trial data, a cost-effectiveness analysis during the time period of 12 months from both perspectives of the UK National Health Service and the societal is presented. Main outcome measure is an incremental cost per quality-adjusted life-year (QALY). RESULTS: From the perspective of the U.K. National Health Service, yoga intervention yields an incremental cost-effectiveness ratio of £13,606 per QALY. Given a willingness to pay for an additional QALY of £20,000, the probability of yoga intervention being cost-effective is 72%. From the perspective of the society, yoga intervention is a dominant treatment compared with usual care alone. This result is surrounded by fewer uncertainties-the probability of yoga being cost-effective reaches 95% at a willingness to pay for an additional QALY of £20,000. Sensitive analyses suggest the same results that yoga intervention is likely to be cost-effective in both perspectives. CONCLUSION: On the basis of this trial, 12 weekly group classes of specialized yoga are likely to be a cost-effective intervention for treating patients with chronic or recurrent low back pain.

Yoga for chronic low back pain: a randomized trial.

BACKGROUND: Previous studies indicate that yoga may be an effective treatment for chronic or recurrent low back pain. OBJECTIVE: To compare the effectiveness of yoga and usual care for chronic or recurrent low back pain. DESIGN: Parallel-group, randomized, controlled trial using computer-generated randomization conducted from April 2007 to March 2010. Outcomes were assessed by postal questionnaire. (International Standard Randomised Controlled Trial Number Register: ISRCTN 81079604) SETTING: 13 non-National Health Service premises in the United Kingdom. PATIENTS: 313 adults with chronic or recurrent low back pain. INTERVENTION: Yoga (n = 156) or usual care (n = 157). All participants received a back pain education booklet. The intervention group was offered a 12-class, gradually progressing yoga program delivered by 12 teachers over 3 months. MEASUREMENTS: Scores on the Roland-Morris Disability Questionnaire (RMDQ) at 3 (primary outcome), 6, and 12 (secondary outcomes) months; pain, pain self-efficacy, and general health measures at 3, 6, and 12 months (secondary outcomes). RESULTS: 93 (60%) patients offered yoga attended at least 3 of the first 6 sessions and at least 3 other sessions. The yoga group had better back function at 3, 6, and 12 months than the usual care group. The adjusted mean RMDQ score was 2.17 points (95% CI, 1.03 to 3.31 points) lower in the yoga group at 3 months, 1.48 points (CI, 0.33 to 2.62 points) lower at 6 months, and 1.57 points (CI, 0.42 to 2.71 points) lower at 12 months. The yoga and usual care groups had similar back pain and general health scores at 3, 6, and 12 months, and the yoga group had higher pain self-efficacy scores at 3 and 6 months but not at 12 months. Two of the 157 usual care participants and 12 of the 156 yoga participants reported adverse events, mostly increased pain. LIMITATION: There were missing data for the primary outcome (yoga group, n = 21; usual care group, n = 18) and differential missing data (more in the yoga group) for secondary outcomes. CONCLUSION: Offering a 12-week yoga program to adults with chronic or recurrent low back pain led to greater improvements in back function than did usual care. PRIMARY FUNDING SOURCE: Arthritis Research UK.

Emollients, education and quality of life: the RCPCH care pathway for children with eczema.

OBJECTIVES: The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies. The eczema pathway focuses on defining the competences to improve the equity of care received by children with eczema. METHOD: The eczema pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including paediatricians, allergists, dermatologists, specialist nurses, dietician, patients' representatives and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. It was also reviewed by a wide range of stakeholders. RESULTS: The results are presented in three sections: the evidence review, mapping and the core knowledge document. The various entry points to the ideal pathway of care are defined from self-care through to follow-up. There is considerable emphasis on good skin care and when allergy problems should be dealt with. The pathway algorithm and associated competences can be downloaded from http://www.rcpch.ac.uk/allergy/eczema. CONCLUSIONS: Effective eczema management is holistic and encompasses an assessment of severity and impact on quality of life, treatment of the inflamed epidermal skin barrier, recognition and treatment of infection and assessment and management of environmental and allergy triggers. Patient and family education which seeks to maximise understanding and concordance with treatment is also important in all children with eczema.

Electronic reminders did not improve postal questionnaire response rates or response times: a randomized controlled trial.

OBJECTIVE: We aim to evaluate the effectiveness of electronic reminders (ERs) to improve the response rates and time to response of postal questionnaires in a health research setting. STUDY DESIGN AND SETTING: This pragmatic randomized controlled trial (RCT) was nested within a multicenter RCT of yoga for lower back pain. Participants who provided an electronic mail address and/or mobile phone number were randomized to receive an ER or no reminder (controls) on the day they were due to receive a follow-up questionnaire. RESULTS: One hundred twenty-five participants (32 males and 93 females) mean age 46 (standard deviation: 11, range: 20-65) were randomized to ER (n=62) or controls (n=63). Overall 85.6% of participants returned postal questionnaires (87.1% ER group and 84.1% from controls). No significant differences were found between the two groups for response rate (difference between groups=3.0%, 95% confidence interval [CI]=-10, 16; P=0.64) or time to response after adjusting for age, gender, and treatment allocation (χ(2) ([3df])=7.10; P=0.07). CONCLUSION: In the present RCT, we found little evidence for the effectiveness of ERs to increase response rates or time to respond for the return of questionnaires in this study population group.

A randomised controlled trial of yoga for the treatment of chronic low back pain: results of a pilot study.

OBJECTIVE: To conduct a pilot trial of yoga for the treatment of chronic low back pain (LBP) to inform the feasibility and practicality of conducting a full-scale trial in the UK; and to assess the efficacy of yoga for the treatment of chronic low back pain. DESIGN: A pragmatic randomised controlled trial was undertaken comparing yoga to usual care. PARTICIPANTS: Twenty participants who had presented to their GP with chronic low back pain in the previous 18 months were recruited via GP records from one practice in York, UK. INTERVENTIONS: Twenty patients were randomised to either 12 weekly 75-min sessions of specialised yoga plus written advice, or usual care plus written advice. Allocation was 50/50. MAIN OUTCOME MEASURES: Recruitment rate, levels of intervention attendance, and loss to follow-up were the main non-clinical outcomes. Change as measured by the Roland and Morris disability questionnaire was the primary clinical outcome. Changes in the Aberdeen back pain scale, SF-12, EQ-5D, and pain self-efficacy were secondary clinical outcomes. Data were collected via postal questionnaire at baseline, 4 weeks, and 12 weeks follow-up. RESULTS: Of the 286 patients identified from the GP database, 52 (18%) consented and returned the eligibility questionnaire, out of these 20 (6.9%) were eligible and randomised. The total percentage of patients randomised from the GP practice population was 0.28%. Ten patients were randomised to yoga, receiving an average of 1.7 sessions (range 0-5), and 10 were randomised to usual care. At 12 weeks follow-up data was received from 60% of patients in the yoga group and 90% of patients in the usual care group (75% overall). No significant differences were seen between groups in clinical outcomes apart from on the Aberdeen back pain scale at four weeks follow-up where the yoga group reported significantly less pain. CONCLUSION: This pilot study provided useful data and information to inform the design and development of a full-scale trial of yoga for CLBP in the UK. A key finding is the calculation of GP practice total list size required for patient recruitment in a full-scale trial, and the need to implement methods to increase class attendance.

Acupuncture for irritable bowel syndrome: a protocol for a pragmatic randomised controlled trial.

BACKGROUND: There is insufficient evidence on the effectiveness of acupuncture for irritable bowel syndrome (IBS) for conclusions to be drawn. Given the current interest in acupuncture by patients, it is in the public interest to establish more rigorous evidence. Building on the positive findings from a pilot study, in this paper we present the protocol for a fully-powered trial designed to establish whether or not acupuncture is effective and cost-effective. METHODS/DESIGN: In this pragmatic randomised controlled trial we will randomise patients recruited directly from GP databases to either 10 sessions of acupuncture plus usual GP care or to usual GP care alone. The primary clinical outcome will be the IBS Symptom Severity Score (SSS) (maximum score 500) at three months, and at 12 month assessing whether there is an overall benefit. We estimate the sample size required to detect a minimum clinical difference at 90% power and 5% significance to be 188 patients. To allow for loss to follow up we will recruit 220 patients drawn from an estimated primary care population of 140 000. Analysis will be by intention-to-treat, and multiple imputation is to be used for missing data.In a nested qualitative study using in-depth interviews, we will explore how patients, acupuncturists, and GPs explain and subsequently understand acupuncture to work. We will use purposive sampling to identify patients and flexible topic guides for the interviews. The data analysis will lead to a thematic description of how patients and practitioners explain how acupuncture works, and whether or not the explanations influence treatment outcome and/or referrals.We will undertake a cost-effectiveness analysis at 12 months by comparing resource use in the two groups with any treatment benefit. We will use the EQ-5D to measure health-related quality of life and convert into quality adjusted life years (QALYs). We will generate cost effectiveness acceptability curves (CEACs) exploring the probability that acupuncture will produce an acceptable cost per QALY at different cost-effectiveness thresholds. DISCUSSION: The trial has received NHS ethics approval and recruited 233 patients between November 2008 and June 2009. Results are expected in 2011. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

A pragmatic multi-centred randomised controlled trial of yoga for chronic low back pain: trial protocol.

UNLABELLED: A systematic review revealed three small randomised controlled trials of yoga for low back pain, all of which showed effects on back pain that favoured the yoga group. To build on these studies a larger trial, with longer term follow-up, and a number of different yoga teachers delivering the intervention is required. This study protocol describes the details of a randomised controlled trial (RCT) to determine the effectiveness and cost-effectiveness of Yoga for chronic Low Back Pain, which is funded by Arthritis Research Campaign (arc) and is being conducted by the University of York. 262 patients will be recruited from GP practices in 5 centres in England. Patients will be randomised to receive usual care or 12 weekly classes of yoga. A yoga programme will be devised that can be delivered by yoga teachers of the two main national yoga organisations in the UK (British Wheel of Yoga and Iyengar Yoga Association (UK)). TRIAL REGISTRATION: Current controlled trials registry ISRCTN81079604 (date registered 30/03/2007).

Nutritional problems related to food allergy in childhood.

Food allergy is becoming an increasing problem worldwide with an estimated 6-8% of children affected at some point in their childhood. The perceived prevalence of food allergy is even higher with an estimated 20% of children adhering to some form of elimination diet. Against this background, accurate diagnosis is essential to prevent the imposition of unnecessarily restrictive diets on young children. Raising clinical awareness amongst health professionals as to the clinical characteristics, epidemiology, investigation, and management of food allergic disorders is key to tackling this growing problem. In this article, three separate cases of children with poor nutrition and secondary morbidity are presented, highlighting the varying scenarios in which these conditions can be encountered. In the first child, the features clinically displayed were hypocalcemic seizures and rickets due to prolonged breast feeding, poor weaning, and inadequate dietary supplementation. The second case reveals the dangers of complementary diagnostic allergy testing leading to poor nutrition as a consequence of an unsupervised elimination diet. The last report describes a child with multiple food allergies, failure to thrive, and protein losing enteropathy to highlight the diversity of nutritional problems faced by allergists and to underline the importance of specialist dietetic input in the management of a child with food allergy.

Risk of acquired drug resistance during short-course directly observed treatment of tuberculosis in an area with high levels of drug resistance.

BACKGROUND: Data on the performance of standardized short-course directly observed treatment (DOTS) of tuberculosis (TB) in areas with high levels of drug resistance and on the potential impact of DOTS on amplification of resistance are limited. Therefore, we analyzed treatment results from a cross-sectional sample of patients with TB enrolled in a DOTS program in an area with high levels of drug resistance in Uzbekistan and Turkmenistan in Central Asia. METHODS: Sputum samples for testing for susceptibility to 5 first-line drugs and for molecular typing were obtained from patients starting treatment in 8 districts. Patients with sputum smear results positive for TB at the end of the intensive phase of treatment and/or at 2 months into the continuation phase were tested again. RESULTS. Among 382 patients with diagnoses of TB, 62 did not respond well to treatment and were found to be infected with an identical Mycobacterium tuberculosis strain when tested again; 19 of these patients had strains that developed new or additional drug resistance. Amplification occurred in only 1.2% of patients with initially susceptible or monoresistant TB strains, but it occurred in 17% of those with polyresistant strains (but not multidrug-resistant strains, defined as strains with resistance to at least isoniazid and rifampicin) and in 7% of those with multidrug-resistant strains at diagnosis. Overall, 3.5% of the patients not initially infected with multidrug-resistant TB strains developed such strains during treatment. Amplification of resistance, however, was found only in polyresistant Beijing genotype strains. CONCLUSIONS: High levels of amplification of drug resistance demonstrated under well-established DOTS program conditions reinforce the need for implementation of DOTS-Plus for multidrug-resistant TB in areas with high levels of drug resistance. The strong association of Beijing genotype and amplification in situations of preexisting resistance is striking and may underlie the strong association between this genotype and drug resistance.

Common structural basis for constitutive activity of the ghrelin receptor family.

Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G(q), phospholipase C pathway was approximately 50% of their maximal capacity as determined through inositol phosphate accumulation. These two receptors also showed very high constitutive activity in activation of cAMP response element-driven transcription. GPR39 displayed a clear but lower degree of constitutive activity through the inositol phosphate and cAMP response element pathways. In contrast, GPR39 signaled with the highest constitutive activity in respect of activation of serum response element-dependent transcription, in part, possibly, through G(12/13) and Rho kinase. Antibody feeding experiments demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically be tuned up and down depending on the size and hydrophobicity of the side chain in position VI:16 in the context of an aromatic residue at VII:09 and a large hydrophobic residue at VII:06. It is concluded that the three ghrelin-like receptors display an unusually high degree of constitutive activity, the structural basis for which is determined by an aromatic cluster on the inner face of the extracellular ends of TMs VI and VII.

Hope: metaphorically speaking.

In a recent Gadamerian hermeneutic study, photography and in-depth interviews were used as key methods to explicate the phenomenon of hope. Whilst using photography within qualitative research has become increasingly popular over the last decade, little has been written about how to introduce photographs as conversation enhancers or how photographs have the capacity to unleash both conceptual and linguistic metaphors. This article gives insights into the experience of using photographs to illuminate the phenomenon of hope and identifies metaphors that were revealed through the participants' photographs.

Learning to take charge: women's experiences of living with endometriosis.

This paper describes aspects of a study that was conducted to determine women's needs for information related to laparoscopy for endometriosis. Sixty-one women attended focus groups, during which they described endometriosis as a disease of multiple losses: of relationships, of career and of a sense of self-worth. The women indicated that the pathway to diagnosis and treatment had been long and unnecessarily difficult. Many women said that they had reached a point where they decided enough was enough: the medical merry-go-round had to finish. They had to become assertive, take control and decide for themselves how they were going to manage their disease and their quality of life. For all but one woman in the study, complementary therapies were vital. For some women, alternative therapies had replaced allopathic medicine completely. Complementary/alternative therapies were a mechanism for regaining control.