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Mean GFR (inulin clearance) was significantly lower in older people with heart failure (92 ml/min/1 purchase viagra soft 50mg overnight delivery erectile dysfunction premature ejaculation treatment. The longitudinal studies contained mixed populations in that not all participants were followed up for the full duration of the study generic 50 mg viagra soft with amex erectile dysfunction 38 years old. The lower kidney function described in one study of older people may be due to unrecognised kidney disease generic 50mg viagra soft visa yellow 5 impotence. Nevertheless it was recommended that the interpretation of GFR measurements should not normally be affected by the age of the person and that a low value should prompt the same response regardless of age purchase viagra soft 100 mg visa erectile dysfunction doctors raleigh nc. The GDG agreed that a decline in GFR of more than 2 ml/min/1. The GDG recommended that, when interpreting the rate of decline of eGFR, it was also necessary to consider the baseline level of kidney function and the likelihood that kidney function would reach a level where renal replacement therapy would be needed if the rate of decline was maintained. When assessing the rate of decline in eGFR, the GDG agreed that a minimum of 3 measurements in not less than 90 days was required (depending on the initial level of eGFR). If a large and unexplained fall in GFR was observed, more frequent monitoring would be needed. Changes in GFR must be interpreted in light of the evidence on biological and assay variability in serum creatinine measurements, which is estimated at 5%. A calculation based on this would suggest that a decline in eGFR of 10 ml/min/1. However, given that a decline in eGFR of more than 2 ml/min/1. The list of possible factors associated with progression does not consider how differences in access to healthcare and poverty may influence the initiation and progression of CKD. Specifically, neither early life influences governing foetal development and low birth weight nor childhood factors contributing to the emergence of hypertension and diabetes are considered here. In those that do progress, the subsequent mortality and morbidity risks rise exponentially, as do the associated healthcare costs. A reduced GFR is also associated with a wide range of complications such as hypertension, anaemia, renal bone disease, malnutrition, neuropathy and reduced quality of life. It is therefore important to clarify exactly what factors are associated with CKD progression, and which are remediable or potentially modifiable, in order to intervene at the earliest possible stage and improve the associated adverse outcomes. The literature was reviewed to examine additional promoters of renal disease progression: cardiovascular disease, acute kidney injury, obesity, smoking, urinary tract obstruction, ethnicity, and chronic use of non-steroidal anti-inflammatory drugs (NSAIDs). There were no studies examining acute kidney injury or urinary tract obstruction on progression of CKD. In a pooled analysis of the ARIC Study and Cardiovascular Health Studies (CHS), kidney function decline (serum creatinine increase ≥0. A diabetic cohort of smokers (N=44, mean age 47 years, 86% had baseline proteinuria >0. Progression to ESRD was compared between males who smoked for 0–5 pack-years (N=73), 5–15 pack years (N=28), or >15 pack years (N=43). It was difficult to determine whether these participants had CKD at baseline. One small, open-label RCT compared changes in creatinine clearance and adverse events with chronic use of ibuprofen, piroxicam, or sulindac in adults aged over 65 years with (CrCl <70 ml/min, N=15) or without renal insufficiency (CrCl >70 ml/min, N=14) 177. In two Spanish case control studies, cases (people who had progressed to ESRD, N=520) were age-, sex- and hospital-matched with controls (hospital patients who had not progressed to ESRD, N=982) and the effects of chronic use of salicylates, pyrazolones and non-aspirin NSAIDs on progression to ESRD were analysed. This relationship persisted after adjustment for diabetes type or control, retinopathy, age, BMI, ACEI use, BP, proteinuria. Proteinuria increased in both smokers and non-smokers, but there were NS differences between the two groups. When ACEI use was taken into account, the association between smoking and progression to ESRD was NS. The mean rise in serum creatinine in Indo-Asian people was significantly greater than in African-Caribbean or Caucasians. Compared with white people with baseline hypertension (N=426,300), black people with baseline hypertension (N=51,016) were 2. Compared with white people with neither baseline hypertension nor diabetes (N=4,651,490), black people with neither hypertension nor diabetes at baseline (N=34,916) were 3. However, 1 month treatment of piroxicam or sulindac was associated with a significant decrease in creatinine clearance. Users of pyrazolones had NS risk of ESRD compared with nonusers. Users of non-aspirin NSAIDs had NS risk of ESRD compared with nonusers. Sub-analysis showed regular use of aspirin compared with non-use of aspirin was significantly associated with increased risk of chronic renal failure in people with diabetic nephropathy, glomerulonephritis, nephrosclerosis, or hereditary renal disease. The GDG also accepted that nephrotoxic drugs may affect progression. Of particular concern are the possible acute and chronic effects of NSAIDs which are available without prescription. Acute use of NSAIDs can lead to an acute and usually reversible fall in GFR but chronic use at therapeutic doses could be associated with progression of CKD. It was recommended that if chronic use of NSAIDs was considered clinically necessary the effect on GFR should be monitored and the drugs should be stopped if there is evidence of progressive CKD. The evidence about possible adverse effects of aspirin was felt to be confounded by the use of aspirin in patients with cardiovascular disease which is a known risk factor for progression of CKD. The evidence on the effects of smoking and ethnicity on the risk of progression was not conclusive but was sufficiently suggestive to merit highlighting within a recommendation. The evidence on the effects of obesity on the risk of progression was unconvincing and did not require highlighting within a recommendation. Despite the lack of evidence for urinary outflow tract obstruction for progression of CKD, the GDG consensus was that obstruction to outflow would lead to progression of CKD. Therefore it was agreed that urinary outflow tract obstruction should be considered as a risk factor. These risk factors are: q cardiovascular disease q proteinuria q hypertension q diabetes q smoking q black or Asian ethnicity q chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) q urinary outflow tract obstruction. R29 In people with CKD the chronic use of NSAIDs may be associated with progression and acute use is associated with a reversible fall in glomerular filtration rate (GFR). Exercise caution when treating people with CKD with NSAIDs over prolonged periods of time. Monitor the effects on GFR, particularly in people with a low baseline GFR and/or in the presence of other risks for progression. The answer to this predominantly lies in 3 main areas: diagnosis and treatment of treatable kidney disease, identification and control of risk factors for progression of CKD and planning for renal replacement therapy in patients progressing to end stage renal disease. The area that has deservedly received the most attention is planning for renal replacement therapy. There is abundant literature detailing the negative effect of late referral of patients with advanced CKD. Late referral leads to increased morbidity and mortality, increased length of hospital stay, and increased costs. The dominant factor though is insufficient time to prepare the patient for dialysis, particularly the establishment of permanent vascular access for haemodialysis.

Yes Yes Yes No Preliminary No Yes Financial Long-term risk medical incentive? No donor Yes CM V titer Yes Risk positive or Risk of acceptable? No Yes Proceed with No No Screening for Yes Proceed with evaluation diabetes evaluation negative? FIGURE 12-32 Prelim inary evaluation of a living prospective donor discount 50 mg viagra soft with amex erectile dysfunction watermelon. The FIGURE 12-33 prospective donor m ust be m ade aware of the possible costs Assessing risks generic 50 mg viagra soft overnight delivery erectile dysfunction 16 years old. O lder age m ay place the living prospective donor at associated with donation discount viagra soft 50mg amex impotence effects on relationships, including travel to and from the greater surgical risk and m ay be associated with reduced graft sur- transplantation center and tim e away from work purchase viagra soft 100 mg free shipping erectile dysfunction injections cost. The prospective donor m ust be inform ed of donor m ust undergo a psychological evaluation to ensure the both the short-term surgical risks (very low in the absence of car- donation is voluntary. A prelim inary m edical evaluation should diovascular disease and other risk factors) and the long-term conse- assess the risks of transm itting infectious diseases with the kid- quences of having only one kidney. W ith regard to long-term risks, ney, eg, infection with hum an im m unodeficiency virus (H IV) it should be considered whether there is a fam ilial disease that the and cytom egalovirus (CM V). These questions are often m ost pertinent for relatives of patients with diabetes. Results of 27 an Am erican Society of Transplantation survey of the United N etwork for O rgan Sharing centers showed that m any centers 22 either use no specific age exclusion criteria or have no policy. In a meta-analysis combining 48 studies of the long-term effects of reduced renal mass in humans, Screening living prospective donors for diabetes. Results of the sur- no evidence was found of a progressive decline in renal function vey of the United N etwork for O rgan Sharing centers showed that after a 50% reduction in renal mass. Indeed, a small but statistically m ost centers exclude patients with a m ildly elevated fasting blood significant increase occurred over time in the glomerular filtration sugar (FBS) and patients with norm al FBS but an abnorm al glucose rate. A small increase in urine protein excretion occurred; however, tolerance test (GTT). M ost centers exclude donors with m ild type the rate of increase per decade was less than that generally considered II diabetes. A small increase in systolic blood pressure was noted; however, it was not enough to lead to an increase in the incidence of hypertension. Thus, it appears that the long-term risks of kidney donation are very small. Shown are multiple linear regression coefficients and 95% confidence intervals. Failure of the confidence interval to include zero indicates P < 0. Results of the survey of the United Network for Organ 60 Sharing centers showed that most exclude 54 prospective donors who require antihyper- 50 tensive medication or whose BP is persistent- ly elevated over 130/80 mm Hg. However, most centers do not exclude living prospec- tive donors who occasionally have BP read- 40 ings over 130/80 mm Hg or patients with so-called white coat hypertension. Normal renal Yes Relative with No imaging and low hereditary No Yes risk for ADPKD? No Yes Consider alternative No donor Blood pressure Yes No high normal? Proceed with evaluation History of No Yes kidney stones Yes No Yes Consider Evaluation indicates Isolated Proceed with alternative hematuria donor No low risk? Yes Evaluate evaluation No Yes FIGURE 12-39 Risk acceptable? Risks to the related donor when the recipient has familial renal dis- ease. Donors for relatives with autosomal dominant polycystic kidney disease (ADPKD) may be permitted to donate if over 25 years old and FIGURE 12-38 results on renal imaging are negative for cysts. Some younger persons may be permitted to donate if genetic studies indicate that the risk for Proteinuria, hypertension, or kidney stones in living prospective subsequent ADPKD is very low. Prospective donors with pyuria must be evaluated for possible hereditary nephritis can be donors if they do not have hematuria. Proteinuria is generally M ale relatives with hematuria cannot be donors. Hypertension also must be considered without hematuria may donate; however, women of child-bearing age at least a relative contraindication to donation. Patients with a history who might be carriers must consider the possibility of someday donat- of nephrolithiasis but no current or recent stones m ay be considered ing a kidney to a child of their own with the disease. Female relatives for donation after first undergoing urologic and metabolic evaluations with hematuria should not donate when other evidence of renal dis- for stones. Occasionally, donors with isolated microhema- turia (not hereditary) and a negative evaluation may be suitable donors. Renal artery angiography is perform ed to define the anatom y of the renal artery Donor-specific No system and exclude other previously undetected abnorm alities. Recent studies have shown that spiral com puterized tom ography Yes can replace angiography without loss of sensitivity or specificity and with less risk and inconvenience to the prospective donor. Consider No Cross-match Yes Angiography (From Kasiske and coworkers; with perm ission. W hen there are no suitable living donors, recipients are 90 placed on the cadaveric waiting list. The transplantation center m ust always decide whether a particular cadaveric kidney being 80 offered for transplantation is suitable for the individual recipient. The shortage of organs and long waiting tim es have caused m any 70 centers to accept kidneys from older donors and kidneys that m ay be dam aged. Data from the United N etwork for O rgan Sharing 60 clearly dem onstrate the decreased graft survival rates of kidneys 50 from older donors. As a com prom ise, som e advocate using kidneys from older donors for older recipients. In any case, so-called marginal 40 kidneys should be offered to recipients with appropriate inform ed Age n t1/2 consent. Scientific Registry for Transplant transplant candidates: clinical practice guidelines. J Am Soc N ephrol Recipients and the O rgan Procurem ent and Transplantation N etwork– 1995, 6:1–34. J Am Soc N ephrol Resources and Services Adm inistration, U. Cecka JM : The UN O S Scientific Renal Transplant Registry. Gjertson DW : A m ulti-factor analysis of kidney graft outcom es at one Transplants 1996. Los Angeles: and five years posttransplantation: 1996 UN O S Update. In Clinical UCLA Tissue Typing Laboratory, 1997:1–14. Periera BJG, W right TL, Schm id CH , Levey AS: The im pact of pre- transplantation hepatitis C infection on the outcom e of renal trans- 10.

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It was a large buy discount viagra soft 100 mg erectile dysfunction doctors in tallahassee, multisite psychother- apy clinical trial for outpatients who met the DSM-IV crite- Although the simplest peripheral blocking approach of pas- ria for cocaine dependence order viagra soft 100 mg fast delivery best erectile dysfunction pills at gnc. For 480 randomized patients discount viagra soft 100mg line erectile dysfunction nclex, sively injecting polyclonal antibodies to cocaine into a four treatments were compared over an 18-month period cheap viagra soft 100 mg without prescription erectile dysfunction doctor houston. One treat- ies would not last very long and might be of limited use as ment also added cognitive therapy, one added supportive- a sustained treatment. For any type of relapse prevention, expressive psychodynamic therapy, and one added individ- the immune response elements must remain at relatively ual drug counseling. The final group had drug counseling high levels for periods of several weeks or months, which alone. Two specific interaction hypotheses, one involving is best done by active immunization (86). However, three psychiatric severity and the other involving degree of antiso- other approaches using catalytic antibodies, monoclonal cial personality characteristics, were examined, but no major passive antibodies, or injections of butrylcholinesterase have findings related to these hypotheses have been found (88, some promise (87). Either of these was intensive, including 36 possible individual sessions and effects can cause a very significant reduction in the high or 24 group sessions for 6 months. All four of these approaches can also be monthly during active treatment and at 9 and 12 months combined and used together with the pharmacotherapies after baseline. Primary outcome measures were the Addic- described above. The only approach that has been tested tion Severity Index–Drug Use Composite score and the in humans is active immunization (86). The initial animal number of days of cocaine use in the past month. Compared studies showed excellent production of a highly specific an- with the two psychotherapies and with group drug counsel- tibody to cocaine. With active immunization the amount ing (GDC) alone, individual drug counseling plus GDC of inhibition of cocaine entering the brain ranged from 30% showed the greatest improvement on the Addiction Severity to 63% at 30 seconds after cocaine injection in rats. Individual group coun- amount of inhibition was sufficient to extinguish cocaine seling plus GDC was also superior to the two psychothera- self-administration in the rat model. In the initial human study of this vaccine, it was well Hypotheses regarding the superiority of psychotherapy to tolerated with virtually no side effects using a dose of 1,000 GDC for patients with greater psychiatric severity and the g given with two booster injections over a 3-month period superiority of cognitive therapy plus GDC compared with (88). The vaccine produced substantive quantities of anti- supportive-expressive therapy plus GDC for patients with body that was related to both the dose of vaccine and the antisocial personality traits or external coping style were not number of booster injections. Thus, compared with professional psychother- potential efficacy in relapse prevention for abstinent cocaine apy, a manual-guided combination of intensive individual abusers appear warranted. PSYCHOTHERAPIES Cognitive Behavioral Therapy (CBT) Professional Psychotherapy vs. Drug In spite of these overall discouraging results, cognitive be- Counseling havioral treatments have been among the most frequently Because of the limited efficacy of pharmacotherapy, the suc- evaluated psychosocial approaches for the treatment of sub- cess of behavioral and psychotherapies is important to con- stance use disorders and have a comparatively strong level sider. To date, more than 24 ran- use of professional therapies such as cognitive behavioral domized controlled trials have evaluated the effectiveness of therapy and supportive expressive therapies has been exam- cognitive behavioral relapse prevention treatment on sub- ined. Second, contingency management as a form of behav- stance use outcomes among adult tobacco smokers and alco- ioral therapy has gotten much attention and reasonable suc- hol, cocaine, marijuana, opiate, and other types of substance cess. These therapies have nowbeen extensively studied and abusers (93). Overall, these studies suggest that the average are increasingly being examined as treatments that might be effect size for CBT compared with control or comparison complemented by emerging pharmacotherapies. Review and many be more readily available to community pro- of this group of studies suggests that, across substances of grams. This body of literature also suggests that out- aimed at administering the drugs, even in the absence of comes in which CBT may hold particular promise include physical dependence (95). Thus, the A reviewof this series of studies can be found in Carroll goal of drug abuse treatment is to decrease behavior main- (93). CM procedures are one method of ment goal of abstinence and relapse prevention, CBT treat- accomplishing this goal, by presenting rewards or incentives ment has two critical components. A functional analysis is simply documented drug use (negative contingencies), or a combi- an exploration of cocaine use with respect to its antecedents nation of the two. The second critical component of CBT Higgins and colleagues (95–97) have demonstrated that is skills training. In CBT, a substantial portion of every CM procedures in combination with a community rein- session is devoted to the teaching and practice of coping forcement approach (CRA) facilitate initial abstinence in skills; in fact, CBT can be thought of as a highly individual- primarily cocaine-dependent persons. In the first, 12-week ized training program that helps cocaine abusers unlearn study (95), the CM procedure consisted of vouchers with old habits associated with cocaine abuse and learn or relearn a monetary value, which were presented upon evidence of more healthy skills and habits. The vouchers increased in value for every consecutively coping skills, changing reinforcement contingencies, foster- drug-free urine and were exchangeable for client-therapist ing management of painful affects, and improving interper- agreed-upon retail items and activities related to treatment sonal functioning. Treatment retention was significantly higher in the In a study comparing supportive therapy to CBT for behavioral treatment than standard drug counseling group. Cocaine outcomes were weeks 1 to 12 and lottery tickets in weeks 13 to 24 were comparable whether the patient received CBT or ClM, or presented contingent upon documented drug abstinence. Similarly, 68% and 42% of the clients in the behav- fewer urine screens positive for cocaine when treated with ioral treatment group achieved at least 8 and 16 weeks, CBT compared with ClM. CBT also was more effective respectively, of continuous cocaine abstinence as opposed than supportive ClM in retaining depressed subjects in to 11% and 5% in the standard drug abuse counseling treatment and in reducing cocaine use (94). In the third, 24-week study (97), cocaine-dependent been useful for medication development as a platform for individuals were randomized to receive either behavioral clinical trials because it meets the guidelines for an effective treatment without incentives or behavioral treatment with platform. Specifically, it is strong enough to hold patients incentives (i. The group that received the incentives showed signif- for any medication effects. As counterexamples, treatments icantly greater treatment retention (75% vs. Overall, rates of abstinence without any medications, but can serve the findings of these studies suggest that incentives contin- as excellent means to inducing initial abstinence. Contingency Management Procedures This voucher system also has been examined in a 12-week Contingency management (CM) procedures are based on clinical trial for its ability to facilitate cocaine abstinence in a behavioral perspective of drug abuse, which views drugs methadone-maintained cocaine abusers (98,99). The con- as powerful reinforcers maintaining high rates of behavior tingency group subjects achieved significantly longer dura- 1470 Neuropsychopharmacology: The Fifth Generation of Progress tions of sustained abstinence than yoked-controls (mean of motivation may be more cost-effective than increasing the 5. These vouchers may contribute to demoralization and a lack of findings suggest that vouchers also can be used as incentives perceived self-efficacy for succeeding in stopping drug use for drug abstinence in opioid-dependent cocaine abusers and thus contribute to a cycle of drug use and failure. One issue with CM dependence: (a) CM is of limited efficacy in this population. This issue CM is costly and not supported by current funding mecha- of continued efficacy after stopping medications has been nisms. Be- has yet to be fully explored, but recent reviews suggest it cause vouchers are used to support treatment goals, thera- may have a modest effect size of 0. These restrictions impose con- siderable program costs over and above the costs of the vouchers. The delay between the time the reinforcement SUMMARY (purchase of goods or services) is provided and the time that the behavior being reinforced (abstinence, as evidenced No medications are currently approved by the Food and by a drug-free urine) occurs may decrease the value to the Drug Administration (FDA) for cocaine dependence, but patient (but not the actual program cost) of the reinforce- we have developed several leads for medications based on ment. The efficacy of CM in studies with cocaine-depen- our understanding of the neurobiology and clinical phe- dent patients also appears to be considerably more modest nomenology of stimulants. Based on neurobiological abnor- at best than in the earlier studies.

This counterintuitive result is most likely a result of collinearity; as shown in Table 48 order viagra soft 50 mg impotence diabetes, behaviours and strategies was negatively correlated with negative food markers buy generic viagra soft 100 mg online erectile dysfunction commercials. However purchase viagra soft 100 mg free shipping erectile dysfunction doctor in hyderabad, in the context of the other MLQ variables purchase viagra soft 50mg online erectile dysfunction treatment stents, this association became positive (β was 0. Such seemingly paradoxical cases have been described in the literature134 and are most likely due to collinearity with other predictor variables or the operation of suppressor variables. Table 47 shows that behaviours and strategies and confidence and motivation were correlated to an extent (r = 0. Further exploration of these composite variables could clarify which items are responsible for these effects. Summary We developed and evaluated a self-report tool, the MLQ, which aimed to capture changes in knowledge, cognitions and behaviours that could explain changes in weight gain. The MLQ contains items that are relevant, acceptable and feasible for 9- to 10-year-olds to complete in a timely manner and it has undergone psychometric testing, although future additional evaluation of the MLQ could include further tests for reliability and construct validity. Five composite variables emerged from the evaluation of the MLQ and these were used as the mediating variables in the two longitudinal path analyses. The first analysis was for the number of weekday unhealthy foods consumed per day (weekday negative food markers at 18 months) and showed statistical evidence for full mediation as the previous significant effect of the intervention on this outcome variable was no longer present (p = 0. This result suggests that the composite variables arising from the MLQ could provide a possible explanation of how the intervention generated the observed differences in dietary behaviour. However, further exploration could clarify this explanation. The analysis for the number of weekday energy dense snacks consumed per day at 18 months revealed partial mediation (p = 0. Overall, it is noted that the full and partial mediation effects were both close to the cut-off point for statistical significance (p = 0. The findings arising from our use of composite variables require cautious interpretation; we are able only to conclude that children have changed in a combination of ways for two of the secondary outcomes in the trial. Future work could include more theoretically based modelling work (which would be possible given the theoretical underpinning of many of the items in the MLQ) as well as cluster analyses135 to investigate which specific mediator and which moderator variables might predict healthy outcomes in the whole HeLP cohort. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 99 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROCESS EVALUATION Conclusions from the process evaluation Data from the process evaluation show that HeLP was delivered as designed in all 16 intervention schools, with high uptake and engagement from schools, children and their families across the socioeconomic spectrum. The mediation analyses show that the intervention effects on the consumption of weekday energy-dense snacks were mediated by knowledge and two composite variables, namely family approval/behaviours and child attitudes and confidence and motivation, whereas the intervention effect on weekday consumption of unhealthy foods (negative food markers) was mediated by the same variables as well as the composite variable behaviours and strategies. We found no evidence of a difference in BMI SDS at 24 months or that participating in HeLP reduced the likelihood that children would be overweight or obese compared to children not receiving the intervention. Similarly, no differences between the intervention and control groups were observed in either anthropometric measures or physical activity objectively assessed using accelerometers at 18 months post baseline. Self-reported weekly average consumption of different types of energy-dense snacks was lower in those attending intervention schools (0. These differences were largely accounted for by reported differences in weekday consumption. The cost of implementing HeLP was estimated at approximately £210 per child. Assumptions are reported regarding the proportions of children needing to move weight category for cost-effectiveness to be achieved using NICE cost-per-QALY methodology. The review identified 139 intervention studies that had weight-related outcomes, of which 115 were located in the primary school. The 37 studies that were purely school-based and did not have a family component showed a low strength of evidence for reducing BMI, BMI SDS, prevalence of obesity and overweight, percentage body fat, waist circumference and skinfold thickness. However, studies that also included a family component provided moderate evidence of effectiveness, with half reporting statistically significant beneficial intervention effects. Other systematic reviews and meta-analyses also suggest that school-based obesity prevention interventions can have a modest effect on BMI SDS and it is unclear whether such effect sizes (typically < 0. We are not aware of any recent, well-conducted, school-based obesity prevention RCTs, using objective outcome measures, for this age group, that have shown a clinically relevant effect on adiposity measures at 2-year follow-up. A very recent school-based trial (Active for Life-year 5)16 involving 60 schools and > 2000 children (aged 9–10 years), which aimed to increase physical activity, reduce sedentary behaviour and increase fruit and vegetable consumption at 2-year follow-up, found no effect of the intervention on any of these primary outcomes or on weight status. Furthermore, the exploratory trial showed changes in diet and physical activity behaviours and weight status; however, these were not replicated in the main trial. In addition, HeLP was delivered as designed in all intervention schools with very high levels of engagement, as was also seen in the exploratory trial. The findings from the process evaluation allow us to be confident that the difference in results between the exploratory and the definitive trial are not due to scale-up issues of delivery. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 101 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION AND CONCLUSIONS differential effect of the intervention between the two cohorts on the primary outcome, indicating that this logistical requirement did not affect the overall findings, and our follow-up rates at 18 and 24 months were similar across both trials. Understanding the lack of effectiveness Conducting health promotion interventions within schools has the obvious potential advantage of being able to reach virtually all children. The behaviours that underlie the development of obesity and overweight in children and adolescents result from a complex interaction of individual, family and social factors. This is particularly relevant for children of primary school age, as their ability to influence their diet and activity is directly limited by decisions made by their parents/carers, as well as being affected by wider social influences. We therefore aimed to develop an intervention that would influence not only the children themselves, but also their parents and the school environment, as we felt that this would have a higher likelihood of being effective. Our review of existing evidence suggested that multifaceted interventions were more likely to be effective when they addressed both diet and exercise, were of significant duration and involved the family, although the strength of these conclusions was limited owing to the paucity of existing high-quality studies. We were also aware that a common reason for failure in health promotion programmes is a failure to persuade the target group to participate and to stay involved, so strategies to achieve engagement by children, parents and schools were fundamental in the design of both the intervention and the trial. In addition, for public health interventions to have an impact, they need to be deliverable without disrupting normal activities and at an affordable cost. We therefore worked closely with children from the target age group, parents, teachers and education advisors at all stages of the design. We assessed the extent to which children, parents and teachers actually engaged with the programme using prespecified criteria for engagement, as well as conducting focus groups with children and interviews with parents and teachers. The results suggested very high levels of engagement across all socioeconomic groups and considerable enthusiasm for the programme. We succeeded in achieving extremely high levels of participation: only 34 out of 1371 children opted out of the trial and only 80 out of 1324 who started the study were lost to follow-up, and hence > 94% of children provided anthropometric data at 2 years and we have accelerometry data at 18 months post baseline on 84% of children (3 weekdays and 1 weekend day). The lack of any effect of the intervention on our primary outcome measure is particularly disappointing given the high levels of engagement and that the programme was developed with substantial stakeholder involvement and reflected the current best evidence regarding techniques to change behaviour. There is a number of potential explanations: we recognise the importance of wider family and social factors in driving health behaviours, which may limit the potential effects of interventions that are delivered primarily at the level of the individual.