General practice referral of 'at risk' populations to community leisure services: applying the RE-AIM framework to evaluate the impact of a community-based physical activity programme for inactive adults with long-term conditions.

BACKGROUND: In the UK a high proportion of adults with long-term conditions do not engage in regular physical activity. General practice (GP) referral to community-based physical activity is one strategy that has gained traction in recent years. However, evidence for the real-world effectiveness and translation of such programmes is limited. This study aimed to evaluate the individual and organisational impacts of the 'CLICK into Activity' programme - GP referral of inactive adults living with (or at risk of) long-term conditions to community-based physical activity. METHODS: A mixed methods evaluation using the RE-AIM framework was conducted with data obtained from a range of sources: follow-up questionnaires, qualitative interviews, and programme-related documentation, including programme cost data. Triangulation methods were used to analyse data, with findings synthesised across each dimension of the RE-AIM framework. RESULTS: A total of 602 individuals were referred to CLICK into Activity physical activity sessions. Of those referred, 326 individuals participated in at least one session; the programme therefore reached 30.2% of the 1080 recruitment target. A range of individual-, social-, and environmental-level factors contributed to initial physical activity participation. Positive changes over time in physical activity and other outcomes assessed were observed among participants. Programme adoption at GP surgeries was successful, but the GP referral process was not consistently implemented across sites. Physical activity sessions were successfully implemented, with programme deliverers and group-based delivery identified as having an influential effect on programme outcomes. Changes to physical activity session content were made in response to participant feedback. CLICK into Activity cost £175,000 over 3 years, with an average cost per person attending at least one programme session of £535. CONCLUSIONS: Despite not reaching its recruitment target, CLICK into Activity was successfully adopted. Positive outcomes were associated with participation, although low 6- and 12-month follow-up response rates limit understanding of longer-term programme effects. Contextual and individual factors, which may facilitate successful implementation with the target population, were identified. Findings highlight strategies to be explored in future development and implementation of GP referral to community-based physical activity programmes targeting inactive adults living with (or at risk of) long-term conditions.

Process evaluation of the Bristol girls dance project.

BACKGROUND: The Bristol Girls Dance Project was a cluster randomised controlled trial that aimed to increase objectively measured moderate-to-vigorous physical activity (MVPA) levels of Year 7 (age 11-12) girls through a dance-based after-school intervention. The intervention was delivered in nine schools and consisted of up to forty after-school dance sessions. This paper reports on the main findings from the detailed process evaluation that was conducted. METHODS: Quantitative and qualitative data were collected from intervention schools. Dose and fidelity were reported by dance instructors at every session. Intervention dose was defined as attending two thirds of sessions and was measured by attendance registers. Fidelity to the intervention manual was reported by dance instructors. On four randomly-selected occasions, participants reported their perceived level of exertion and enjoyment. Reasons for non-attendance were self-reported at the end of the intervention. Semi-structured interviews were conducted with all dance instructors who delivered the intervention (n = 10) and school contacts (n = 9) in intervention schools. A focus group was conducted with girls who participated in each intervention school (n = 9). RESULTS: The study did not affect girls' MVPA. An average of 31.7 girls participated in each school, with 9.1 per school receiving the intervention dose. Mean attendance and instructors' fidelity to the intervention manual decreased over time. The decline in attendance was largely attributed to extraneous factors common to after-school activities. Qualitative data suggest that the training and intervention manual were helpful to most instructors. Participant ratings of session enjoyment were high but perceived exertion was low, however, girls found parts of the intervention challenging. CONCLUSIONS: The intervention was enjoyed by participants. Attendance at the intervention sessions was low but typical of after-school activities. Participants reported that the intervention brought about numerous health and social benefits and improved their dance-based knowledge and skills. The intervention could be improved by reducing the number of girls allowed to participate in each school and providing longer and more in-depth training to those delivering the intervention. TRIAL REGISTRATION: ISRCTN52882523 Registered 25th April 2013.

A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk.

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ≈ 20 ng ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16,705 asthmatics and 30,809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

Optimal use of regression models in genome-wide association studies.

The performance of linear regression models in genome-wide association studies is influenced by how marker information is parameterized in the model. Considering the impact of parameterization is especially important when using information from multiple markers to test for association. Properties of the population, such as linkage disequilibrium (LD) and allele frequencies, will also affect the ability of a model to provide statistical support for an underlying quantitative trait locus (QTL). Thus, for a given location in the genome, the relationship between population properties and model parameterization is expected to influence the performance of the model in providing evidence for the position of a QTL. As LD and allele frequencies vary throughout the genome and between populations, understanding the relationship between these properties and model parameterization is of considerable importance in order to make optimal use of available genomic data. Here, we evaluate the performance of regression-based association models using genotype and haplotype information across the full spectrum of allele frequency and LD scenarios. Genetic marker data from 200 broiler chickens were used to simulate genomic conditions by selecting individual markers to act as surrogate QTL (sQTL) and then investigating the ability of surrounding markers to estimate sQTL genotypes and provide statistical support for their location. The LD and allele frequencies of markers and sQTL are shown to have a strong effect on the performance of models relative to one another. Our results provide an indication of the best choice of model parameterization given certain scenarios of marker and QTL LD and allele frequencies. We demonstrate a clear advantage of haplotype-based models, which account for phase uncertainty over other models tested, particularly for QTL with low minor allele frequencies. We show that the greatest advantage of haplotype models over single-marker models occurs when LD between markers and the causal locus is low. Under these situations, haplotype models have a greater accuracy of predicting the location of the QTL than other models tested.

A multi-centred sequential trial comparing PEGASUS, an intervention to promote shared decision making about breast reconstruction with usual care.

Decision making about breast reconstruction (BR) is complex. The Patients' Expectations and Goals: Assisting Shared Understanding of Surgery (PEGASUS) intervention aims to support shared decision making by helping women and clinicians clarify and discuss their expectations around reconstructive surgery. We conducted a multi-centred sequential trial comparing PEGASUS (n = 52) with usual care (UC) (n = 86) in women considering reconstruction, who completed outcome measures at baseline, and 3, 6 and 12 months post-surgery. The primary outcome was BR-specific quality of life (Breast-Q) 6 months post-intervention. Secondary outcomes were health-related quality of life (EQ-5D-5L), capabilities (ICECAP-A) and decisional regret, compared using t-tests and Cohen's d. Comparative analyses revealed no significant differences between groups in Breast-Q scores at any time point, except for a favourable effect for UC on psychological well-being at 3 months (t = -2.41, p = .019, d= -0.59). Intervention participants reported significantly higher, therefore improved, ICECAP-A (t = -2.13, p = .037, d = -0.45) and EQ VAS (t = -2.28, p = .026, d = -0.49) scores at 12 months compared to UC. Decisional regret was significantly lower in the PEGASUS group compared to the UC group at 6 months (t =2.06, p = .044, d= -0.51), but this was not sustained at 12 months. In conclusion, the PEGASUS intervention offers some benefits to women considering BR. At times, women experienced less decisional regret, improved health-related quality of life and capability well-being. Findings are discussed in the light of fidelity testing and embedding PEGASUS into practice.

Caring for survivors of childhood cancers: the size of the problem.

Many survivors of childhood cancer have significant health problems due to their illness or treatment. This population-based study examines the number of long-term survivors, their disabilities and consequent long-term care needs. Survival rates for children diagnosed with cancer between 1960 and 1999 in the West Midlands, United Kingdom (UK), were used to estimate future long-term survivor numbers. Treatment and late effects data on a cohort of patients surviving for more than 5 years were used to consider continuing care needs. Between the 1960s and 1990s, 5-year survival increased from 23% to 70%. There were 98 5-year survivors in 1970, and numbers may exceed 2,100 by the end of 2005. Most (at least 61%) survivors in the West Midlands Region have one or more chronic medical problems and may require multidisciplinary care. We conclude that, in order to determine how to provide cost-effective care for this increasing population, protocol delivered management with audit is needed.

Levels of adrenal and gonadal hormones in rhesus monkeys during chronic hypokinesia.

The purpose of this study was to evaluate the effect of chronic immobilization on the hypophysial-adrenal and hypophysial-gonadal axes of adult male rhesus monkeys and the effect such manipulation has on the ability of these axes to respond to exogenous corticotropin, gonadotropin, and GnRH administration. A comparison was also made of the effects of immobilization on testosterone secretion at periods of low (April) and high (November) gonadal activity in this animal. Adult male rhesus monkeys were immobilized in a horizontal position for periods of up to 20 days during March/April. The function of the hypophysial-adrenal and hypophysial-gonadal axes was studied by monitoring plasma levels of cortisol, 17-hydroxylated precursors, 11 deoxycortisol, and testosterone during the period of restraint. Groups of immobilized and control animals also received iv injections of ACTH, FSH, and LH or LHRH on day 18 of the experiment. An additional group of animals was immobilized for 20 days, but did not receive exogenous hormone treatment. This group was used for comparison of seasonal differences in testosterone secretion with another group of animals subjected to the same treatment in November. During the first 3 h of immobilization, levels of cortisol, 17-hydroxylated precursors, and 11-deoxycortisol increased markedly from initial levels. Cortisol levels remained elevated for 3 days, whereas levels of the other three adrenal hormones declined to near-initial levels within 24 h. Testosterone levels declined steadily during the first 6 h of immobilization in males studied at a time of high testicular activity (November), while an increase during the first hour of restraint followed by a decline during the next 3 days were observed in males studied during a period of low testicular activity (April). Animals injected with ACTH on day 18 of immobilization had cortisol levels similar to those of control animals, but other groups of animals restrained for a similar period exhibited a lower level of plasma testosterone than controls after the injection of FSH and LH or LHRH. These data suggest that adaptation to stress results in a reduced demand for corticosteroid production and that the adrenals of chronically stressed animals are capable of responding to exogenous corticotropin, or alternatively, the immobilization imposed was stressful for only a limited time, and after a few days, animals no longer reacted as in response to stress. Also, secretion of testosterone in male monkeys is markedly influenced by the functional state of the gonads at the time of stress initiation.

The identification of peptide sequences of human chorionic gonadotropin containing a conformational epitope.

A series of overlapping peptides were synthesized representing the entire amino acid sequence of the beta-subunit of human chorionic gonadotropin (hCG) and these were reacted with a monoclonal antibody shown to be specific for hCG. One linear peptide (residues 40-52 of the sequence) reacted significantly with the monoclonal antibody but a conjugate of this peptide to diphtheria toxoid (DT) failed to elicit significant levels of antibodies reactive to hCG in rabbits. The subsequent preparation of an extended peptide (residues 38-57) in which the two cysteines were oxidized to form a loop peptide yielded a highly immunogenic antigen when conjugated to DT. Antibody levels reactive with hCG from loop peptide immunizations of rabbits exceeded those found after immunization with a 37 residue peptide representing the carboxyl terminus of the beta-hCG subunit. The antisera did not react with pituitary glycoprotein hormones with similar sequences.

Characterization of solubilized microvillous membrane proteins and glycoproteins from human placental syncytiotrophoblast.

Microvillous membrane fractions from human term placentae were prepared by differential centrifugation. Extration of membranes with PBS-EDTA or KCI removed soluble cytoplasmic components and serum proteins excepting trace amounts of albumin and transferrin. PAGE-SDS revealed 11 components in the Triton solubilized crude fraction after PBS-EDTA extraction. Membrane components solubilized with Triton were not fractionated by gel filtration on Bio-Gel A-50 m but DEAE-cellulose chromatography partially resolved these components. Three fractions were obtained by stepwise elution of absorbed materials using increasing concentrations of NaCl in the equilibrating buffer. These fractions were characterized using SDS-PAGE. The material unabsorbed to the DEAE contained two components of small molecular weight and one of them showed a positive PAS stain. The first eluted protein peak showed nine components, seven of which stained with PAS. The bulk of glycoproteins with molecular weights greater than 130 000 daltons were found in this fraction. The second eluted peak from DEAE was rich in components with molecular weights less than 42 000 daltons. Four components in this fraction were not identified in the other two ion-exchange fractions. Bands representing mobilities of albumin, transferrin and alkaline phosphatase were observed in DEAE-cellulose fractions; however, 12 components of unknown structure were revealed.

Clonal diversity of Ig and T-cell receptor gene rearrangements in childhood B-precursor acute lymphoblastic leukaemia.

The majority of paediatric B precursor acute lymphoblastic leukaemias in children are derived from a single transformed haematopoietic cell with complete or partial VDJ recombination within the immunoglobulin heavy chain gene. A high frequency of patients also show rearrangements within TCRdelta and TCRgamma loci and in up to 40% of children there is an excess of immune system gene rearrangements compared with the number of identified alleles of immune system genes, suggesting the presence of multiple leukaemic subclones -clonal diversity. It has been observed by us and other investigators that in individual patients the pattern of immune system gene rearrangements often changes between presentation and relapse. In order to explore the possibility that clonal diversity plays a biological role during disease progression we optimised methods for subclone detection and analysed the prognostic significance of clonal diversity among 75 children with B precursor-ALL. Our results suggest that clonal diversity plays a role in disease progression as patients with oligoclonal disease showed a significantly shorter disease free survival than patients with monoclonal disease. This trend was of particular importance in the 'standard risk' group of ALL where aggressive disease could not be recognised by other means. In addition, generation of independent subclones from an early, non-rearranged tumour progenitor appears to be a common feature among leukaemias with aggressive clinical behaviour. We speculate on the type of genetic factors which may participate both in the generation of subclones and also in wider genomic instability and which are likely to be required for the aggressive clinical phenotype in children with ALL.

Reduction of fertility in female baboons immunized with lactate dehydrogenase C4.

Immunization of female rabbits and mice with the sperm-specific isozyme of lactate dehydrogenase, LDH-C4, significantly reduced their fertility. Similar studies have been extended to nonhuman primates. Two female baboons, immunized with human LDH-C4, produced low antibody titers. These titers were markedly enhanced by booster injections of murine LDH-C4. An additional seven female baboons responded with relatively high antibody titers after receiving murine LDH-C4 as both priming and booster dosages. All nine females received injections of murine LDH-C4 at varying times determined by serum titer levels during fertility studies. These antisera reacted with human, mouse, and baboon LDH-C4. In a series of breeding experiments, 22 of 30 matings, or 73%, were infertile as compared with 28% in control matings. This contraceptive effect of the vaccine containing LDH-C4 was related to antibody titer and was reversible. Normal pregnancies ensued in animals in which the titer declined after termination of booster injections of vaccine.

Antifertility effects of immunization of female baboons with C-terminal peptides of the beta-subunit of human chorionic gonadotropin.

Fifteen adult female baboons were immunized with a conjugate of tetanus toxoid coupled with a synthetic carboxy-terminal peptide of the beta-subunit of human chorionic gonadotropin and another 15 were immunized with tetanus toxoid. Freund's complete adjuvant was used in all immunizations. All females were placed with males of proven fertility during the third menstrual cycle after the primary immunization and those not sustaining pregnancy were mated in two additional consecutive cycles. Four pregnancies occurred following 42 matings in the conjugate-immunized group and 15 pregnancies resulted from 21 matings in the tetanus toxoid-immunized animals. Low levels of antibodies reactive to baboon chorionic gonadotropin were found in the pregnant animals in the conjugate-immunized group.

Humoral response of normal and athymic (nude) mice to human choriogonadotropin immunogens.

The production of antibodies against human choriogonadotropin (hCG) was studied in normal and athymic (nu/nu) mice of two strains (C57/BL and Balb/c), injected with native (whole) hCG or an immunogen consisting of a synthetic hCG beta COOH-terminal peptide, residues 109-145, conjugated to diphtheria toxoid and mixed with a synthetic muramyl dipeptide analog (nor-MDP) as adjuvant. Both the short-term effect of native hCG dissolved in saline and injected IM (primary response), and the long-term effect of the native hCG and of the hCG immunogen dissolved in saline, emulsified in squalene-Arlacel A, and injected SC as a depot injection (secondary or memory response), were considered. The results obtained indicate that native hCG may be classified as a T-cell independent antigen in the sense that it can elicit low levels of IgM antibodies on a short term basis in athymic mice that have either no or very low T-cell levels. In long-term studies using hCG and the hCG immunogen no antibodies could be detected in athymic mice 14 days after a booster inoculation given 28 days after primary immunization, a regimen that produced high levels of antibodies in normal mice. Because of their inability to sustain humoral responses to native hCG as well as to other hCG immunogens, athymic mice seem well suited for in vivo studies of some of the biological effects of hCG.

The role of carboxy-terminal portion of beta subunit of human chorionic gonadotropin in human immunodeficiency virus infection.

Human chorionic gonadotropin (hCG) and the beta subunit of this dimer glycoprotein hormone (beta hCG) have been reported by us to inhibit HIV replication. In order to identify the active site responsible for the antiviral activity, twelve overlapping peptides spanning across beta hCG were examined for their effect against HIV-caused cell death. Although the NH2-terminus of beta hCG appeared to contribute to activity, the core region was biologically inert. The most potent activity was observed with the fragment representing the carboxy-terminus of beta hCG. The dose response curve to serial dilutions of the peptide, containing amino acid residues 106-145, had a bell-shaped appearance - characteristic of hCG and beta hCG. The peak of activity corresponded to 100 ng/ml - the dose at which two thirds of virus-exposed MT-4 T lymphocytes survived. None of the tested peptides were toxic to MT-4. While the mechanism of action remains unclear, the results suggest that the COOH-terminal portion, unique to beta hCG, confers anti-HIV activity.

Population screening for neonatal liver disease: potential for a community-based programme.

OBJECTIVES: To evaluate a community-based screening programme for detecting neonatal liver disease by the quantitation of conjugated bilirubin in blood. SETTINGS AND METHODS: Prospective cohort/observational study using spare plasma from routinely collected liquid neonatal screening specimens from babies born in Birmingham over a two-year period. Babies with a conjugated bilirubin above 18 mumol/l and comprising more than 20% of the total bilirubin were followed up. A total of 27654 neonates were tested in the community, with a further 2425 samples from babies hospitalised at the time of the test. RESULTS: In the community-based series, 84.7% of the specimens received were analysed, the remainder being unusable mainly because of gross haemolysis (8.6%) or insufficient sample (5.8%). In 107 neonates the results were above the cut-off limits (0.46% of the number analysed). Of these, 12 had persistently abnormal results, 11 of whom had confirmed liver disease. The liver diseases detected included neonatal hepatitis (n=6), extra-hepatic biliary atresia (n=2), hypopituitarism (n=1), alpha-1-antitrypsin deficiency (n=1) and Alagille syndrome (n=1). The sensitivity and specificity of the test for babies in the community were 100% and 99.6%, respectively. CONCLUSIONS: Conjugated bilirubin in plasma measured at 6-10 days is a reliable marker for neonatal liver disease, and a population screening programme based on this method has the potential to improve the survival and quality of life of infants born with liver disease. However, testing as part of the neonatal screening programme will prove practical only if the method can be adapted to use dried blood spots.

Rhinomanometry in the selection for adenoidectomy and its relation to preoperative radiology.

Recent work has shown that resolution of otitis media with effusion (OME) following adenoidectomy may be related to certain preoperative radiographic parameters. This study was performed to investigate the relationship between the total nasal resistance (TNR), adenoid volume and the radiographic palatal airway and adenoid depth in children with OME. Fifty-six children underwent anterior active rhinomanometry and 40 completed the investigation. There was a significant association between the Palatal Airway and the TNR, and in the 27 who subsequently underwent adenoidectomy this was nearly so with respect to adenoid volume and TNR. The relationship demonstrated was not strong enough for TNR to be of use in selection of children for adenoidectomy based on radiographic parameters. Rhinomanometry can be difficult and time-consuming to perform in children. In its present form it is unlikely to be of routine clinical use in this context.

Alcohol use among older hospital patients: findings from an Australian study.

Data on alcohol use were obtained from structured interviews with hospital patients aged 65 and over. The cross-sectional sample (sex by age by region) was drawn from three hospitals in New South Wales, Australia. Multivariate statistics and chi-square tests of proportion were used to analyse the data. Significant main effects were found for sex and age. The majority (65%) of the sample had consumed alcohol in the past year. Males were more likely than females to be current drinkers and also had a higher mean weekly alcohol intake than females. There was a significant fall in alcohol consumption with age. More males (25%) than females (6%) were found to be hazardous/harmful users of alcohol, and those in the 65-74-year age group had a higher incidence of problem alcohol use (20.8%) than those aged 75-84 (9.8%) and over 85 (4.9%). The results suggest a comparatively high incidence of problem alcohol use among older hospital patients and indicate the need for consumer education.

Artificial neural networks and survival prediction in ovarian carcinoma.

The standard use of known survival predictors for ovarian cancer in clinical practice are primarily based on disease stage. This does not permit a real individualization of a patient's potential outcome. This study assessed the value of neural networks to refine the prediction of survival based only on information gleaned at primary surgery. The possibility exists that such methods may permit further elucidation of outcome and influence management.

Nasal mucociliary clearance and resolution of otitis media with effusion in children following adenoidectomy.

Numerous workers have studied the relationship between nasal mucociliary clearance and adenoid removal in terms of nasal function. This study was performed to investigate the role of preoperative saccharin clearance time and velocity determination in selecting children with established otitis media with effusion (OME) for adenoidectomy. Testing was not found to be particularly reproducible and there was no statistically significant relationship between mucociliary parameters and the otoscopic resolution of effusion.