Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration.

BACKGROUND: Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. METHODS: This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. RESULTS: After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. CONCLUSION: Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Advanced approach to activity evaluation for released-active forms of antibodies to interferon-gamma by enzyme-linked immunoassay.

Selection of a suitable assay to measure the activity of drugs based on released-active forms (RA forms of Abs) is an important step during their investigation. In this study, ELISA was utilized to examine the effect of RA forms of Abs to interferon gamma on the interaction between monoclonal anti-interferon gamma antibodies and human interferon gamma. The data showed that such RA forms of Abs are able to modulate the antibody interaction with interferon gamma, and it was suggested that the observed influence of RA forms of Abs on 'antibody-antigen' interaction could be used to analyze the activity of this kind of drugs.

Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09(H1N1) in murine model.

The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile, and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0.13, 0.2, 0.4, 0.8 ml/mouse/day) in a murine model of acute pneumonia induced by influenza virus pandemic strain A/California/07/09 (H1N1). Administration of the drug at the two highest doses led to: a reduction in the virus infectious titer in lung tissue up to 4.2 lgEID50/20 mg of tissue; infected animals' life prolongation up to 6.7 days; an increase in the survival rate of up to 40% and a decrease in morphological signs of inflammation when compared to the control animals. In this study, the dose-response effect of Anaferon for Children was demonstrated on mice for the first time. This finding is especially important for drugs with a principally novel mechanism of action like drugs based on released-active forms of antibodies. J. Med. Virol. 89:759-766, 2017. © 2016 Wiley Periodicals, Inc.

The phenomenon of released-activity. Reply on comment on Don et al.: Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09(H1N1) in murine model.

This text is aimed to provide the readers with detailed information about phenomenon of released-activity and reply on the specific risen questions.

Short-term efficacy and safety of new biological agents targeting the interleukin-23-T helper 17 pathway for moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis.

A new generation of biologics targeting the interleukin-23-T helper 17 pathway has been developed. This study aimed to assess the short-term effectiveness and safety of these new agents using a network meta-analysis. Twenty-seven randomized clinical trials (10 629 patients) were identified by a comprehensive systematic literature review (PROSPERO 2015: CRD42015025472). Quality of evidence was assessed following Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations approach. Efficacy and safety outcomes at weeks 10-16 were compared using a random-effects network meta-analysis within a frequentist framework to estimate pooled odds ratios (ORs) of direct and indirect comparisons among the therapeutic options. There were six direct drug-to-drug comparisons in the network, with a high degree of consistency between the direct and indirect evidence. From the available evidence, infliximab 5 mg kg-1 every 8 weeks [OR 118·89, 95% confidence interval (CI) 60·91-232·04] and secukinumab 300 mg every 4 weeks (OR 87·07, 95% CI 55·01-137·82) are shown to be among the most effective short-term treatments, but are ranked as the biologics most likely to produce any adverse event or an infectious adverse event, respectively. Ustekinumab 90 mg every 12 weeks, the third most efficacious treatment (OR 73·67, 95% CI 46·97-115·56), was the only agent that did not show increased risk of adverse events compared with placebo. Treatment recommendations should also consider long-term outcomes and costs.

Long-term cost-effectiveness analysis of endovascular versus open repair for abdominal aortic aneurysm based on four randomized clinical trials.

BACKGROUND: A number of published economic evaluations of elective endovascular aneurysm repair (EVAR) versus open repair for abdominal aortic aneurysm (AAA) have come to differing conclusions about whether EVAR is cost-effective. This paper reviews the current evidence base and presents up-to-date cost-effectiveness analyses in the light of results of four randomized clinical trials: EVAR-1, DREAM, OVER and ACE. METHODS: Markov models were used to estimate lifetime costs from a UK perspective and quality-adjusted life-years (QALYs) based on the results of each of the four trials. The outcomes included in the model were: procedure costs, surveillance costs, reintervention costs, health-related quality of life, aneurysm-related mortality and other-cause mortality. Alternative scenarios about complications, reinterventions and deaths beyond the trial were explored. RESULTS: Models based on the results of the EVAR-1, DREAM or ACE trials did not find EVAR to be cost-effective at thresholds used in the UK (up to £30,000 per QALY). EVAR seemed cost-effective according to models based on the OVER trial. These results seemed robust to alternative model scenarios about events beyond the trial intervals. CONCLUSION: These analyses did not find that EVAR is cost-effective compared with open repair in the long term in trials conducted in European centres. EVAR did appear to be cost-effective based on the OVER trial, conducted in the USA. Caution must be exercised when transferring the results of economic evaluations from one country to another.

Guidance for the gastrointestinal evaluation and management of iron deficiency in Sub-Saharan Africa.

BACKGROUND: Over 30% of the world's population is anaemic, with a significant proportion of these being iron deficient. As iron deficiency (ID) anaemia in men and post-menopausal women is mostly caused by gastrointestinal blood loss or malabsorption, the initial evaluation of a patient with ID anaemia involves referral to a gastroenterologist. The current drive towards patient blood management in sub-Saharan Africa (SSA)prescribes that we regulate not only the use of blood transfusion but also the management of patients in whom the cause of iron loss or inadequate iron absorption is sought. Recommendations have been developed to: (i) aid clinicians in the evaluation of suspected gastrointestinal iron loss and iron malabsorption, and often a combination of these; (ii) improve clinical outcomes for patients with gastrointestinal causes of ID; (iii) provide current, evidence-based, context-specific recommendations for use in the management of ID; and (iv) conserve resources by ensuring rational utilisation of blood and blood products. METHOD: Development of the guidance document was facilitated by the Gastroenterology Foundation of Sub-Saharan Africa and the South African Gastroenterology Society. The consensus recommendations are based on a rigorous process involving 21 experts in gastroenterology and haematology in SSA. Following discussion of the scope and purpose of the guidance document among the experts, an initial review of the literature and existing guidelines was undertaken. Thereafter, draft recommendation statements were produced to fulfil the outlined purpose of the guidance document. These were reviewed in a round-table discussion and were subjected to two rounds of anonymised consensus voting by the full committee in an electronic Delphi exercise during 2022 using the online platform, Research Electronic Data Capture. Recommendations were modified by considering feedback from the previous round, and those reaching a consensus of over 80% were incorporated into the final document. Finally, 44 statements in the document were read and approved by all members of the working group. CONCLUSION: The recommendations incorporate six areas, namely: general recommendations and practice, Helicobacter pylori, coeliac disease, suspected small bowel bleeding, inflammatory bowel disease, and preoperative care. Implementation of the recommendations is aimed at various levels from individual practitioners to healthcare institutions, departments and regional, district, provincial and national platforms. It is intended that the recommendations spur the development of centre-specific guidelines and that they are integrated with the relevant patient blood management protocols. Integration of the recommendations is intended to promote optimal evaluation and management of patients with ID, regardless of the presence of anaemia.

Cost-effectiveness of laparoscopic fundoplication versus continued medical management for the treatment of gastro-oesophageal reflux disease based on long-term follow-up of the REFLUX trial.

BACKGROUND: Laparoscopic fundoplication surgery has been shown to be a cost-effective alternative to continued medical management over 1 year for patients with gastro-oesophageal reflux disease (GORD). The longer-term cost-effectiveness is, however, uncertain. This study evaluated the long-term health benefits, costs and cost-effectiveness of laparoscopic fundoplication compared with continued medical management in patients with GORD. METHODS: Individual patient data were used from the 5-year follow-up of the REFLUX trial, a large multicentre, pragmatic, randomized trial in which 357 patients with GORD for at least 12 months at trial entry were allocated randomly to early laparoscopic fundoplication or continued medical management. Health outcomes were expressed in quality-adjusted life-years (QALYs). A UK National Health Service perspective was used for costs. RESULTS: The group randomized to surgery experienced better health outcomes in each year of follow-up, but the difference narrowed over time. At 5 years, the surgery group had experienced 0.216 (95 per cent confidence interval 0.021 to 0.412) more QALYs but also accrued €1832 (1214 to 2448) more costs. The incremental cost-effectiveness ratio was €8481 per QALY gained. The probability that surgery is the most cost-effective intervention was 0.932 at a threshold of €24,134/QALY (£20,000/QALY). Results were robust to most sensitivity analyses, except where patients with missing data randomized to surgery were assumed to have worse health outcomes. CONCLUSION: Laparoscopic fundoplication is a cost-effective alternative to continued medical management over 5 years. No evidence was found to suggest that the cost-effectiveness of laparoscopic fundoplication diminishes over time.

Modelling the cost-effectiveness of carotid endarterectomy for asymptomatic stenosis.

BACKGROUND: The aim of this study was to model the cost-effectiveness of carotid endarterectomy for asymptomatic stenosis versus medical therapy based on 10-year data from the Asymptomatic Carotid Surgery Trial (ACST). METHODS: This was a cost-utility analysis based on clinical effectiveness data from the ACST with UK-specific costs and stroke outcomes. A Markov model was used to calculate the incremental cost-effectiveness ratio (ICER, or cost per additional quality-of-life year) for a strategy of early endarterectomy versus medical therapy for the average patient and published subgroups. An exploratory analysis considered contemporary event rates. RESULTS: The ICER was £7584 per additional quality-adjusted life-year (QALY) for the average patient in the ACST. At thresholds of £20,000 and £30,000 there was a 74 and 84 per cent chance respectively of early endarterectomy being cost-effective. The ICER for men below 75 years of age was £3254, and that for men aged 75 years or above was £71,699. For women aged under 75 years endarterectomy was less costly and more effective than medical therapy; for women aged 75 years or more endarterectomy was less effective and more costly than medical therapy. At contemporary perioperative event rates of 2·7 per cent and background any-territory stroke rates of 1·6 per cent, early endarterectomy remained cost-effective. CONCLUSION: In the ACST, early endarterectomy was predicted to be cost-effective in those below 75 years of age, using a threshold of £20,000 per QALY. If background any-territory stroke rates fell below 1 per cent per annum, early endarterectomy would cease to be cost-effective.

Effects of Y27632 on keratinocyte procurement and wound healing.

A number of Rho-kinase inhibitors have been developed for various clinical applications. We examined the effects of the Rho-kinase inhibitor Y27632 on keratinocyte proliferation and migration, and found that it promoted primary human keratinocyte proliferation and migration in both monolayer and skin explant cultures. In addition, topical application of Y27632 enhanced cutaneous wound closure in the majority of wounds in mice. The growth and migration effects of Y27632 appeared to be specific to keratinocytes compared with dermal fibroblasts, and required intact Jun kinase function. Y27632 seems to be a promising agent for keratinocyte procurement and wounding healing.

Low positive predictive value of the ABCD2 score in emergency department transient ischaemic attack diagnoses: the South Western Sydney transient ischaemic attack study.

BACKGROUND: The ABCD(2) stroke risk score is recommended in national guidelines for stratifying care in transient ischaemic attack (TIA) patients, based on its prediction of early stroke risk. We had become concerned about the score accuracy and its clinical value in modern TIA cohorts. METHODS: We identified emergency department-diagnosed TIA at two hospitals over 3 years (2004-2006). Cases were followed for stroke occurrence and ABCD(2) scores were determined from expert record review. Sensitivity, specificity and positive predictive values (PPV) of moderate-high ABCD(2) scores were determined. RESULTS: There were 827 indexed TIA diagnoses and record review was possible in 95.4%. Admitted patients had lower 30-day stroke risk (n = 0) than discharged patients (n = 7; 3.1%) (P < 0.0001). There was no significant difference in proportion of strokes between those with a low or moderate-high ABCD(2) score at 30 (1.2 vs 0.8%), 90 (2.0 vs 1.9%) and 365 days (2.4 vs 2.4%) respectively. At 30 days the sensitivity, specificity and PPV of a moderate-high score were 57% (95% confidence interval (CI) 25.0-84.2), 32.2% (95% CI 29.1-35.6) and 0.75% (95% CI 0.29-1.91) respectively. CONCLUSIONS: Early stroke risk was low after an emergency diagnosis of TIA and significantly lower in admitted patients. Moderate-high ABCD(2) scores did not predict early stroke risk. We suggest local validation of ABCD(2) before its clinical use and a review of its place in national guidelines.

Therapeutic potential of highly diluted antibodies in antibiotic-resistant infection.

Klebsiella pneumoniae is one of the main causes of hospital-acquired infections. Its rate of antimicrobial resistance is rapidly increasing, while there are no licensed human vaccines against it. A novel therapeutic approach involves modulation of the host immune response combined with antibiotic treatment. One of the approaches to immunomodulation can be the use of antibodies (Abs) in a specific technological form of high dilutions (hd). The aim of the study was to assess whether hd-Abs could affect the antibacterial activity of AMC against a bacterial strain resistant to it. The study was performed on an in vivo model of K. pneumoniae BAA-1705 multiresistant strain lethal infection in neutropenic RjOrl:Swiss mice. The efficacy of hd-Abs combined with AMC was assessed based on survival and lung bacterial burden. Additionally, we evaluated the direct effect of the drugs on the growth of bacteria in vitro. hd-Abs in combination with AMC increased survival of mice infected with K. pneumoniae up to 50%, whereas all animals in the AMC group died. Hd-Abs had no direct effect on K. pneumoniae sensitivity to AMC in vitro. The survival rate in mice treated with hd-Abs combined with AMC was comparable to that in animals treated with the reference drug gentamicin. Thus, hd-Abs increased the antibacterial activity of AMC against the strain resistant to it. The mechanism of action of hd-Abs remains to be elucidated in future studies.

A METHOD TO IDENTIFY AND LOCALIZE A SINGLE HOT PARTICLE IN THE LUNGS USING AN ARRAY OF HIGH-PURITY GERMANIUM DETECTORS FOR IMPROVED ESTIMATE OF THE DEPOSITED ACTIVITY.

A new method has been developed to identify and localize a single hot particle in the lungs using an array of four high-purity germanium detectors. The method is based upon calculating a set of three count rate ratios (generated by each individual detector in the array) that are evaluated in sequence to designate whether the measured deposition can be associated with a hot particle rather than the default assumption of a uniform activity distribution. Identification and localization of the hot particle are determined from a single in vivo measurement in which detectors are positioned above and below the thorax. The method was tested using an anthropomorphic thorax phantom in which point sources of 241Am, 137Cs and 60Co were individually inserted in the lungs at 15 different locations and were measured using a scanning bed whole-body counter. Depending upon source location and photon energy, a bias of -35% up to +76% could be introduced by falsely assuming a uniform activity distribution in the lungs. This bias would directly translate to an erroneous dose estimate to the lungs. It was demonstrated that by using the appropriate detector efficiencies for the single hot particle, the bias associated with the activity determination is reduced to <10% and ~2% in average.

Recruiting for research on sensitive topics in schools: an experience with Vaxcards, a collectable vaccine card game.

Undertaking recruitment for research in schools is an effective way to recruit young people for research participation but it is not without its challenges. Gaining access and coordinating many levels of different organisations and stakeholders whose cooperation and approval are crucial all add time and sometimes logistical challenges for the research team. In addition, recruiting around sensitive research topics can elicit additional barriers to successful research. The research team aimed to conduct a pragmatic cluster randomised controlled trial involving schools in a local government region in Victoria, Australia, to assess the effect of a vaccination-based educational card game called "Vaxcards" on vaccine consent returns. Schools were contacted via phone and email to determine which staff member would best be a contact point for a face-to-face meeting to discuss the methods and purpose of the study. Email follow-ups were scheduled to follow up non-responsive schools and consent forms. The minimum required sample size was 13. Of 31 eligible schools, 13 were recruited. The research team encountered several unanticipated challenges before achieving the recruitment target. The most common reasons for non-participation were being too busy with other commitments, concerns regarding the topic of vaccination being too sensitive, and concerns that key stakeholders in the school would not approve of the research topic of vaccination. One school required a review by a private research ethics board that rejected the study. Significant hesitancy and misinformation about vaccine science was observed that affected engagement with a small number of schools. This paper highlights the challenges of recruiting schools in the context of public anxieties about vaccines and has several important learning lessons for successful recruitment about sensitive topics. This includes navigating approval processes for research in schools, the importance of local champions, dealing with misinformation and the importance of strong relationships and organisational trust. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001753246 . Prospectively registered on 25 October 2018 8:24:21 AM.

Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully 'switchable' in vivo mouse model of diabetes.

AIMS/HYPOTHESIS: Irreversible arterial damage due to early effects of hypo- or hyperglycaemia could account for the limited success of glucose-lowering treatments in preventing cardiovascular disease (CVD) events. We hypothesised that even brief hypo- or hyperglycaemia could adversely affect arterial gene expression and that these changes, moreover, might not be fully reversible. METHODS: By controlled activation of a 'switchable' c-Myc transgene in beta cells, adult pIns-c-MycER(TAM) mice were rendered transiently hypo- and then hyperglycaemic, after which they were allowed to recover for up to 3 months. Immediate and sequential changes in aortic global gene expression from normal glycaemia through hypo- and hyperglycaemia to recovery were assessed. RESULTS: Gene expression was compared with that of normoglycaemic transgenic and tamoxifen-treated wild-type controls. Overall, expression of 95 genes was significantly affected by moderate hypoglycaemia (glucose down to 2.5 mmol/l), whereas over 769 genes were affected by hyperglycaemia. Genes and pathways activated included several involved in atherogenic processes, such as inflammation and arterial calcification. Although expression of many genes recovered to initial pre-exposure levels when hyperglycaemia was corrected (74.9%), in one in four genes this did not occur. Quantitative reverse transcriptase PCR and immunohistochemistry verified the gene expression patterns of key molecules, as shown by global gene arrays. CONCLUSIONS/INTERPRETATION: Short-term exposure to hyperglycaemia can cause deleterious and persistent changes in arterial gene expression in vivo. Brief hypoglycaemia also adversely affects gene expression, although less substantially. Together, these results suggest that early correction of hyperglycaemia and avoidance of hypoglycaemia may both be necessary to avoid excess CVD risk in diabetes.

Cost-effectiveness of traditional and endovenous treatments for varicose veins.

BACKGROUND: The aim of this study was to evaluate the cost-effectiveness of traditional and endovenous treatments for patients with primary great saphenous varicose veins. METHODS: A Markov model was constructed to compare costs and quality-adjusted life years (QALYs) for great saphenous vein (GSV) reflux. Eight popular treatment strategies were compared up to 5 years. Estimates for the effectiveness of treatments were obtained from published randomized studies and cost values were obtained from published National Health Service (NHS) healthcare resource group tariffs and device manufacturers. Parameter uncertainty was tested using sensitivity analysis and Monte Carlo simulation. RESULTS: Ultrasound-guided foam sclerotherapy (UGFS) had the lowest initial cost, but a higher requirement for further interventions. Day-case surgery (with concomitant treatment of varicosities), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) performed in an outpatient or office setting (with staged treatment of varicosities) were likely to be cost-effective treatment strategies. The incremental cost-effectiveness ratio (ICER) for UGFS (versus conservative care), EVLA (versus UGFS) and RFA (versus EVLA) were £1366, £5799 and £17 350 per QALY respectively. The ICER for traditional surgery (performed on a day-case basis) was £19 012 compared with RFA. Other strategies were not cost-effective using the NHS threshold of £20 000 per QALY. CONCLUSION: Day-case surgery or endovenous ablation using EVLA or RFA performed as an outpatient are likely to be cost-effective treatment strategies for patients with primary unilateral GSV reflux requiring treatment.

Epidemiology of inflammatory bowel disease in sub-Saharan Africa: A review of the current status.

While inflammatory bowel disease (IBD) has been well characterised in the West and other parts of the world, there are little data from sub-Saharan Africa (SSA). To throw light on the current status of IBD in SSA, we performed a systematic review of the literature, extracting relevant publications. We found only 210 documented IBD cases in SSA (excluding South Africa (SA)), which were reported in 34 publications until August 2019. The majority were cases of ulcerative colitis. Only three reports, all from SA, attempted to determine IBD incidence rates. The rest were mostly case reports or small case series; the largest from Nigeria comprised 32 patients. The paucity of documented cases possibly reflects under-diagnosis and under-reporting. Major deficiencies in diagnostic and clinical capacity were noted, which need to be addressed going forward.

Patient chosen gap payments in primary care: Predictions of patient acceptability, uptake and willingness to pay from a discrete choice experiment.

Compulsory co-payments limit access and may compromise quality in primary care. Patient Chosen Gap Payments (PCGPs) allow patients to specify a (voluntary) out-of-pocket contribution, creating an incentive for patient-centred care without the need for complex outcomes-based funding formulae. It is not yet known if widespread use of PCGP services is consistent with consumer preferences. We conducted a discrete choice experiment (DCE) in a sample of the adult Australian general population (n = 1457) during April 2019 to simulate patient choice between alternative primary care services and describe preferences for PCGP services. Participants also completed a supplementary valuation task in which participants reported their intended PCGP contribution for PCGP services. Finally, we conducted policy-simulations to predict market shares when PCGP clinics operate alongside the two existing models of primary care funding in Australia. Results suggest that patients prefer shorter wait time, longer consults, lower compulsory copayments, services with higher patient satisfaction ratings, choice of doctor and $0 suggested voluntary contribution for PCGP services. Policy-simulations suggest that high-quality PCGP services could obtain market share of up to 39% and voluntary contributions of up to $25.36 per service (95%CI: $10.24, $40.47), potentially adding $1.48 billion AUD in revenues and funding for primary care at no cost to government. Low-quality PCGP services are unlikely to capture significant market share and PCGP contributions were lowest for low-quality PCGP services ($12.12, 95%CI: $2.09, $26.34). Further field testing is recommended where (i) patients make consequential choices (e.g. real payments for simulated services), and (ii) dynamic effects on quality of care and utilisation can be observed; particularly in vulnerable populations. We conclude that PCGP services aligned with patient preferences could capture significant market share and substantially increase revenue to general practice.

A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function.

The Drosophila melanogaster gene insulin-like receptor (InR) is homologous to mammalian insulin receptors as well as to Caenorhabditis elegans daf-2, a signal transducer regulating worm dauer formation and adult longevity. We describe a heteroallelic, hypomorphic genotype of mutant InR, which yields dwarf females with up to an 85% extension of adult longevity and dwarf males with reduced late age-specific mortality. Treatment of the long-lived InR dwarfs with a juvenile hormone analog restores life expectancy toward that of wild-type controls. We conclude that juvenile hormone deficiency, which results from InR signal pathway mutation, is sufficient to extend life-span, and that in flies, insulin-like ligands nonautonomously mediate aging through retardation of growth or activation of specific endocrine tissue.