The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.

Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.

Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system.

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer's disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.

Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.

Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.

Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK) signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the functioning and role of the IIS pathway in ageing and metabolism.

Sex hormones differentially influence voluntary running activity, food intake and body weight in aging female and male rats.

The aim of this study was to examine the longer-term effects of reduced gonadal hormones on food intake, food efficiency, voluntary running activity and body weight in mature male and female rats, compared to age-matched controls. We hypothesized that hormonal effects would differ for rats that were not rapidly growing and our results are consistent with this hypothesis. 6-8 month male and female rats were divided into four groups: Female and male control groups and a female and male experimental group. Control groups were intact for 46 weeks. Experimental groups were intact during Phase I (16 weeks), ovariectomized or orchidectomized during Phase II (20 weeks), and received estrogen or testosterone hormone replacement therapy (HRT) during the final Phase III (10 weeks). Food intake and running distance were monitored daily and body weight was recorded weekly for 46 weeks. Contrary to findings for young and growing animals, we did not observe a (1) stabilization of food intake in female rats following OVX, (2) loss of body weight with ORX in males, or (3) complete restoration of running activity in ORX males given testosterone, compared to females given estrogen. Feeding efficiency was not affected by aging in females or males. Loss of estrogen increased energy intake whereas reduced testosterone in males resulted in a negative energy balance. Findings suggest variable hormonal effects for aging male/female rats.

A rehabilitation exercise program to remediate skeletal muscle atrophy in an estrogen-deficient organism may be ineffective.

To determine rehabilitation exercise program effects under hormone deficient (ovariectomy or OVX) and hormone supplemented [OVX + 17-beta estradiol (E2)] conditions. Mature female rats (n = 123) were assigned to OVX or OVX + E2-supplemented groups. OVX and OVX + E2 groups were allocated to one of four conditions: (1) control, (2) hindlimb unweighted (HLU) for 4 weeks to induce muscle atrophy, (3) cage Recovery for 2 weeks after HLU, and (4) Recovery with 2 weeks of rehabilitation exercise program after 4 weeks of HLU. Atrophy following HLU was comparable for OVX and OVX + E2-supplemented rats and was significant in all muscles examined (soleus, tibialis anterior, plantaris, gastrocnemius, quadriceps). Also significant with HLU was the decline in muscle force (P < 0.05) in soleus, plantaris, gastrocnemius and tibialis anterior (quadriceps not tested). There were trends toward return of muscle mass in Recovery OVX and Recovery OVX + E2 groups but only the E2 supplemented OVX rats had return of muscle mass (4/5 muscles studied) with exercise. Peak tetanic tension (Po) returned to control values in the E2 supplemented Exercise rats but not in the unsupplemented Exercise group. For example, gastrocnemius Po for OVX HLU, OVX Recovery and OVX-Exercise groups was 82%*, 82%* and 76%* of control. Gastrocnemius Po for E2 supplemented HLU, Recovery and Exercise groups was 72%*, 95% and 106% of control (*P < 0.05 compared to control). H&E cross-sections from OVX-Exercise rats showed central nuclei. In conclusion, a rehabilitation exercise program to remediate acute atrophy in females appears more effective if E2 is present.

Comparison of passive transfer of immunity in neonatal dairy calves fed colostrum or bovine serum-based colostrum replacement and colostrum supplement products.

OBJECTIVE: To compare serum total protein (sTP) and serum IgG (sIgG) concentrations In neonatal calves administered colostrum or a bovine serum-based colostrum replacement (CR) product followed by a bovine serum-based colostrum supplement (CS) product. DESIGN: Randomized controlled clinical trial. ANIMALS: 18 Jersey and 269 Holstein neonatal heifer calves. PROCEDURES: 141 calves were given 4 L of colostrum in 1 or 2 feedings (first or only feeding was provided≤2 hours after birth; when applicable, a second feeding was provided between 2 and 12 hours after birth). Other calves (n=146) were fed 2 L of a CR product≤2 hours after birth and then 2 L of a CS product between 2 and 12 hours after birth. Concentrations of sTP and sIgG were measured 1 to 7 days after birth. Data from cohorts on individual farms and for all farms were analyzed. RESULTS: Mean sTP and sIgG concentrations differed significantly between feeding groups. In calves fed colostrum and calves fed CR and CS products, mean±SD sTP concentration was 5.58±0.67 g/dL and 5.26±0.54 g/dL, respectively, and mean sIgG concentration was 1,868±854 mg/dL and 1,320±620 mg/dL, respectively. The percentage of calves that had failure of passive transfer of immunity (ie, sIgG concentrations<1,000 mg/dL) was not significantly different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that sequential feeding of bovine serum-based CR and CS products to neonatal calves is an alternative to feeding colostrum for achieving passive transfer of immunity.

Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila.

High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.

The effect of ovariectomy combined with hindlimb unloading and reloading on the long bones of mature Sprague-Dawley rats.

OBJECTIVE: To determine the effect of loss of ovarian function and mechanical loading (ie, inactivity) alone or in combination on bone mass and strength. DESIGN: Mature (aged 6 mo) rats were ovariectomized to induce loss of ovarian function and bone. Hindlimb unloading (HLU) was used to determine the effect of mechanical unloading and reloading on bone mass and strength. Bone mass of the femur and tibia was determined using dual-energy x-ray absorptiometry. Femoral and tibial bone strength was determined by a three-point bending test and by a torsion test. RESULTS: Ovariectomy (OVX) alone decreased total bone mineral density (BMD) in the femur (-5.5%, P=0.03) and tibia (-7.3%, P=0.01) compared with that for sham-operated animals. HLU alone for 4 weeks had no significant effect on bone. Together OVX/HLU accentuated BMD loss in the femur (-10.5%, P<0.01) compared with that for sham-operated animals. The femur was more sensitive than the tibia to the combination of OVX/HLU, indicated by the reduction (-5.3%, P<0.05) of total BMD below that achieved by OVX alone. Torsion tests showed that OVX/HLU but not OVX or HLU alone reduced bone strength. There was a correlation between lower femoral total BMD (r2=0.65, P<0.001) and reduced torque strength. Bone loss did not continue during the 2 weeks of reloading. CONCLUSIONS: OVX accompanied by mechanical unloading results in more rapid and severe bone loss than either OVX or unloading alone and therefore is associated with a greater likelihood of osteoporosis.

Ovariectomy prevents the recovery of atrophied gastrocnemius skeletal muscle mass.

The recovery of atrophied muscle mass in animals is thought to be dependent on a number of factors including hormones, cytokines, and/or growth factor expression. The Akt/mammalian target of rapamycin (mTOR) signaling pathway is believed to be activated by these various factors, resulting in skeletal muscle growth through the initiation of protein synthesis. It was hypothesized that surgical removal of the ovaries (Ovx) may alter activation of the Akt/mTOR signaling pathway, a mechanism necessary for muscle regrowth. To test this, 36 Sprague-Dawley rats underwent Ovx or sham surgeries. A portion of the animals were then subjected to hindlimb unloading (HLU) for 28 days. After HLU, one group of Sham and Ovx rats underwent a 14-day recovery period in which the animals were allowed free cage ambulation. The HLU animals demonstrated approximately 21-27% reduction in medial gastrocnemius muscle mass irrespective of whether the ovaries were intact or not. The Sham animals that were reloaded recovered their atrophied muscle mass; however, the Ovx group failed to recover any of the atrophied muscle mass with reloading. The failure to recover muscle mass in the Ovx group was associated with reduced phosphorylation levels of both Akt and p70s6k, whereas in the Sham recovery animals no reductions were found in Akt phosphorylation and significant increases in p70s6k activation were detected. Finally, no differences were detected in mTOR phosphorylation in any of Sham or Ovx groups. These results suggest that ovariectomy surgeries could be detrimental to the recovery of atrophied muscle mass.

Use of corporate Six Sigma performance-improvement strategies to reduce incidence of catheter-related bloodstream infections in a surgical ICU.

BACKGROUND: Corporate performance-improvement methodologies can outperform traditional ones in addressing ICU-based adverse events. My colleagues and I used Six Sigma methodology to address our catheter-related bloodstream infection (CR-BSI) rate, which considerably exceeded the nationally established median over a 9-year period. We hypothesized that use of Six Sigma methodology would result in a substantial and sustainable decrease in our CR-BSI rate. STUDY DESIGN: All patients were directly cared for by a geographically localized surgical ICU team in an academic tertiary referral center. CR-BSIs were identified by infection control staff using CDC definitions. Personnel trained in Six Sigma techniques facilitated performance-improvement efforts. Interventions included barrier precaution kits, new policies for catheter changes over guide wires, adoption of a new site-preparation antiseptic, direct attending supervision of catheter insertions, video training for housestaff, and increased frequency of dressing changes. After additional data analysis, chlorhexidine-silver catheters were used selectively in high-risk patients. The impact of interventions was assessed by monitoring the number of catheters placed between CR-BSIs. RESULTS: Before the intervention period, 27 catheters were placed, on average, between individual CR-BSIs, a CR-BSI rate of 11 per 1,000 catheter days. After all operations were implemented, 175 catheters were placed between line infections, and average CR-BSI rate of 1.7/1,000 catheter days, a 650% improvement (p < 0.0001). Compared with historic controls, adoption of chlorhexidine-silver catheters in high-risk patients had a considerable impact (50% reduction; p < 0.05). CONCLUSIONS: This represents the first successful application of Six Sigma corporate performance-improvement method impacting purely clinical outcomes. CR-BSI reduction was highly substantial and sustained after other traditional strategies had failed.

Ovariectomy, hindlimb unweighting, and recovery effects on skeletal muscle in adult rats.

INTRODUCTION: The effect of female sex hormones on skeletal muscle is unclear. Reports suggest that female sex hormones have an anabolic effect, have no effect, or are detrimental to skeletal muscle. METHODS: To amplify ovarian hormones' potential effects on skeletal muscle, 6-mo-old virgin intact (sham), ovariectomized (OVX), and ovariectomized plus estrogen (OVX + E2) rats were hindlimb unweighted (HLU) for 4 wk. To investigate estrogen's influence on the recovery process, OVX-HLU, sham-HLU and OVX + E2 HLU rats were cage-recovered for 2 wk following 4 wk of HLU. Changes in muscle mass were determined for the soleus (SOL), extensor digitorum longus (EDL), quadriceps (QUAD), gastrocnemius (GAST), tibialis anterior (TA), plantaris (PLA), and flexor carpi radialis (FCR). Dry weights were determined for GAST and TA. Peak tetanic tension was ascertained in the postural SOL and locomotor PLA. RESULTS: HLU resulted in a significant (p < 0.05) decline in mass of all muscles studied except EDL and FCR. The magnitude of atrophy resulting from suspension was similar between groups including wet and dry muscle mass normalized to bodyweight. Following HLU there were no differences between intact and OVX rats for contractile characteristics. Reloading for 2 wk resulted in recovery of wet muscle mass in intact and OVX + E2 rats for SOL, PLA, GAST, QUAD, and TA and in dry mass for GAST and TA. Reloaded OVX-HLU rats failed to recover wet muscle mass in all but the SOL and failed to recover GAST and TA dry weight. For example, PLA mass values for intact (sham) rats were 350 +/- 33, 284 +/- 41, and 346 +/- 44 mg for the control, HLU, and recovery groups, respectively. PLA values for OVX rats were 378 +/- 29, 316 +/- 30, and 325 +/- 23 mg for the control, HLU, and recovery groups. DISCUSSION: Results suggest that ovarian function influences the recovery of skeletal muscle mass following a period of reduced physical activity.

New graduate nurses' transition to home healthcare: an integrative review.

This article is a review of relevant literature exploring the factors that contribute to new graduate nurses' transition to home healthcare nursing. The results revealed themes that include introducing the nurse to home healthcare nursing, knowledge and confidence, and developing the professional role. The review findings suggest that home healthcare leaders should consider recruiting new graduate nurses to home healthcare nursing and provide a structured orientation program in a supportive and welcoming work environment.

Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila.

The biguanide drug, metformin, commonly used to treat type-2 diabetes, has been shown to extend lifespan and reduce fecundity in C. elegans through a dietary restriction-like mechanism via the AMP-activated protein kinase (AMPK) and the AMPK-activating kinase, LKB1. We have investigated whether the longevity-promoting effects of metformin are evolutionarily conserved using the fruit fly, Drosophila melanogaster. We show here that while feeding metformin to adult Drosophila resulted in a robust activation of AMPK and reduced lipid stores, it did not increase lifespan in either male or female flies. In fact, we found that when administered at high concentrations, metformin is toxic to flies. Furthermore, no decreases in female fecundity were observed except at the most toxic dose. Analysis of intestinal physiology after metformin treatment suggests that these deleterious effects may result from disruptions to intestinal fluid homeostasis. Thus, metformin appears to have evolutionarily conserved effects on metabolism but not on fecundity or lifespan.

Detrimental effects of RNAi: a cautionary note on its use in Drosophila ageing studies.

RNA interference (RNAi) provides an important tool for gene function discovery. It has been widely exploited in Caenorhabditis elegans ageing research because it does not appear to have any non-specific effects on ageing-related traits in that model organism. We show here that ubiquitous, adult-onset activation of the RNAi machinery, achieved by expressing a double stranded RNA targeting GFP or lacZ for degradation, or by increasing expression of Dicer substantially reduces lifespan in Drosophila melanogaster. Induction of GFPRNAi construct also alters the response of lifespan to nutrition, exacerbating the lifespan-shortening effects of food containing a high quantity of yeast. Our study indicates that activation of the RNAi machinery may have sequence-independent side-effects on lifespan, and that caution needs to be exercised when employing ubiquitous RNAi in Drosophila ageing studies. However, we also show that RNAi restricted to certain tissues may not be detrimental to lifespan.

dFOXO-independent effects of reduced insulin-like signaling in Drosophila.

The insulin/insulin-like growth factor-like signaling (IIS) pathway in metazoans has evolutionarily conserved roles in growth control, metabolic homeostasis, stress responses, reproduction, and lifespan. Genetic manipulations that reduce IIS in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse have been shown not only to produce substantial increases in lifespan but also to ameliorate several age-related diseases. In C. elegans, the multitude of phenotypes produced by the reduction in IIS are all suppressed in the absence of the worm FOXO transcription factor, DAF-16, suggesting that they are all under common regulation. It is not yet clear in other animal models whether the activity of FOXOs mediate all of the physiological effects of reduced IIS, especially increased lifespan. We have addressed this issue by examining the effects of reduced IIS in the absence of dFOXO in Drosophila, using a newly generated null allele of dfoxo. We found that the removal of dFOXO almost completely blocks IIS-dependent lifespan extension. However, unlike in C. elegans, removal of dFOXO does not suppress the body size, fecundity, or oxidative stress resistance phenotypes of IIS-compromised flies. In contrast, IIS-dependent xenobiotic resistance is fully dependent on dFOXO activity. Our results therefore suggest that there is evolutionary divergence in the downstream mechanisms that mediate the effects of IIS. They also imply that in Drosophila, additional factors act alongside dFOXO to produce IIS-dependent responses in body size, fecundity, and oxidative stress resistance and that these phenotypes are not causal in IIS-mediated extension of lifespan.

Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.

The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.

Classification of adverse events occurring in a surgical intensive care unit.

INTRODUCTION: We aimed to describe the preventability and provider specificity of surgical intensive care unit (SICU) deaths and complications compared with those in a cohort of trauma patients. METHODS: Data were collected on all trauma and SICU admissions from July 1, 2001, to June 30, 2004, from administrative (Trauma Base and Project Impact) and morbidity databases. Services were protocol driven and staffed by in-house attendings. Performance improvement assessments were made by consensus. Deaths and complications were classified as preventable, potentially preventable, or nonpreventable, and provider-specific or not. Statistical significance was established at the P < .05 level. RESULTS: One hundred sixty-eight deaths (5.6% rate), 464 procedure-related, and 694 non-procedure-related complications were noted in 2969 SICU patients compared with 166 deaths (3.6% rate), 178 procedure-related, and 261 non-procedure-related complications in 4,655 trauma patients. Thirty-one percent of SICU deaths were preventable/potentially preventable compared with 14% of trauma deaths, but only 1.9% was attributable to the SICU provider. SICU complications were less frequently preventable/potentially preventable than in trauma patients (52% versus 61%) and less often provider-specific (5% versus 19%). CONCLUSIONS: SICU complications are deemed preventable less often than in trauma patients and, if so, infrequently incriminate the SICU provider. Preventable and potentially preventable SICU deaths are rarely attributed to SICU care. These data suggest that SICU performance improvement should focus on systems solutions and pre-SICU care.

Amelioration of increased intensive care unit service readmission rate after implementation of work-hour restrictions.

UNLABELLED: In July 2003, we reallocated our resident workforce to address mandated duty-hour restrictions. In the subsequent academic year (AY), surgical intensive care unit (SICU) service readmission rates (RR) doubled. We hypothesized that a targeted intervention could reduce SICU service RR in academic year (AY) 2004-05. METHODS: This study was conducted at an urban teaching hospital before (AY02-03, period 1), during (AY03-04, period 2), and after (AY04-05, period 3) implementation of the Accreditation Council for Graduate Medical Education guidelines. Demographics, RR, and reason were culled from Project Impact and a complications database. SICU staff (dedicated intensivist, two or three fellows, and six residents) remained constant. In periods 2 and 3 (versus 1), ward residents cross-covered > or = 3 services every 5 to 6 nights (versus every 3 in period 1) with physician assistant support (versus none in period 1). During period 3, a focused transfer phone call, charted care summary, and discharge checkup defined the intervention. Interperiod comparisons were by chi2 and t test analysis; p < 0.05 (versus period 1) defined significance. RESULTS: In all, 1,570, 1,705 and 1,681 patients were treated in periods 1, 2, and 3, respectively. There were no demographic or APACHE score differences. RRs were 1.4%, 3.0% and 1.2% in periods 1, 2, and 3, respectively. The percentages of readmissions as a result of ward care were 16.7, 41, and 10%, respectively. The most common readmission indication was respiratory (46% in period 1; 51% in period 2, and 80% in period 3) and was associated with an increased proportion of readmission as a result of patient disease (46% in period 1; 41% in period 2; 80% in period 3). Intervention noncompliance preceded 30% of period 3 readmissions. CONCLUSION: A targeted intervention can reduce the rate of SICU readmission caused by care inadequacies stemming from a resident reallocation strategy.