COntrolling NUTritional Status (CONUT) as Predictive Score of Hospital Length of Stay (LOS) and Mortality: A Prospective Cohort Study in an Internal Medicine and Gastroenterology Unit in Italy.

BACKGROUND: Hospital malnutrition affects nearly 30% of patients in medical wards and correlates with worse outcomes. An early assessment is necessary to stratify the risk of short-term outcomes and mortality. The predictive role of COntrolling NUTritional status (CONUT) score in this context has not yet been elucidated in Western countries. We aimed to test CONUT at admission as a predictive score of hospital outcomes, in an Internal Medicine and Gastroenterology Department of an Italian Tertiary Care University hospital. METHODS: We prospectively enrolled patients admitted to our center, stratifying them into the four CONUT classes (normal = 0-1; mild = 2-4; moderate = 5-8; severe = 9-12 points) according to serum albumin (g/dL), total lymphocyte count (/mm3), and total cholesterol (mg/dL); the primary outcome measure was length of stay (LOS) and the secondary one was in-hospital mortality. RESULTS: Out of a total of 203 patients enrolled, 44 (21.7%) patients had a normal status (0-1), 66 (32.5%) had a mild impairment (2-4), 68 (33.5%) had a moderate impairment (5-8), and 25 (12.3%) a severe impairment (9-12). The mean LOS was 8.24 ± 5.75 days; nine patients died. A moderate-severe CONUT correlated with a higher LOS at the univariate [HR 1.86 (95% CI 13.9-3.47); p < 0.0001] and multivariate analysis [HR 1.52 (95% CI 1.10-2.09); p = 0.01]. The CONUT score was also a predictor of mortality, with an AUC of 0.831 (95% CI 0.680-0.982) and with an optimal cut-off at 8.5 points. Nutritional supplementation within 48 h from admission correlated with lower mortality [OR 0.12 (95% CI 0.02-0.56) p = 0.006]. CONCLUSIONS: CONUT is a reliable and simple predictor of LOS and in-hospital mortality in medical wards.

Incidence and Impact of Refeeding Syndrome in an Internal Medicine and Gastroenterology Ward of an Italian Tertiary Referral Center: A Prospective Cohort Study.

Background: Refeeding syndrome (RS) is a neglected, potentially fatal syndrome that occurs in malnourished patients undergoing rapid nutritional replenishment after a period of fasting. The American Society for Parenteral and Enteral Nutrition (ASPEN) recently released new criteria for RS risk and diagnosis. Real-life data on its incidence are still limited. Methods: We consecutively enrolled patients admitted to the Internal Medicine and Gastroenterology Unit of our center. The RS risk prevalence and incidence of RS were evaluated according to ASPEN. The length of stay (LOS), mortality, and re-admission rate within 30 days were assessed. Results: Among 203 admitted patients, 98 (48.3%) were at risk of RS; RS occurred in 38 patients (18.7% of the entire cohort). Patients diagnosed with RS had a higher mean LOS (12.5 days ± 7.9) than those who were not diagnosed with RS (7.1 ± 4.2) (p < 0.0001). Nine patients (4.4%) died. Body mass index (OR 0.82; 95% CI 0.69−0.97), RS diagnosis (OR 10.1; 95% CI 2.4−42.6), and medical nutritional support within 48 h (OR 0.12; 95% CI 0.02−0.56) were associated with mortality. Conclusions: RS incidence is high among clinical wards, influencing clinical outcomes. Awareness among clinicians is necessary to identify patients at risk and to support those developing this syndrome.

MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis.

Rescue of embryonic lethality in MDM4(-/-) mice through concomitant loss of p53 has revealed a functional partnership between the two proteins. Biochemical studies have suggested that MDM4 may act as a negative regulator of p53 levels and activity. On the other hand, MDM4 overexpression has been reported to stabilize p53 levels and to counteract MDM2-degradative activity. We have investigated the functional role of MDM4 overexpression on cell behavior. In both established and primary cells cultured under stress conditions, overexpression of MDM4 significantly increased p53-dependent cell death, in correlation with enhanced induction of the endogenous p53 protein levels. This phenomenon was associated with induced p53 transcriptional activity and increased levels of the proapoptotic protein, Bax. Further, p53 stabilization was accompanied by decreased association of the protein to its negative regulator, MDM2. These findings reveal a novel role for MDM4 by demonstrating that in non-tumor cells under stress conditions it may act as a positive regulator of p53 activity, mainly by controlling p53 levels. They also indicate a major distinction between the biological consequences of MDM4 and MDM2 overexpression.

MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts.

MDMX is a p53 binding protein, which shares a high degree of homology with MDM2, a negative regulator of the tumor suppressor p53. MDMX has been shown to counteract MDM2-dependent p53 degradation and to stabilize p53 in its inactive form. In this study: we identify two MDMX proteolytic pathways that control its intracellular levels, and show that MDMX post-translational processing may be regulated by p53. Mouse MDMX is cleaved in vitro and in vivo by caspase activity, between aminoacids 358 and 361, producing a p54 minor form. In addition, MDMX is subjected to proteasome-mediated degradation, which concurs to MDMX proteolysis mainly through degradation of p54. A D361A-MDMX mutant, resistant to caspase cleavage, exhibits prolonged intracellular lifetime in comparison to wild-type protein, indicating that caspase cleavage affects stability of MDMX protein probably by modulating its further degradation. Overexpression of exogenous p53 increases the intracellular levels of p54 product. Similarly, activation of endogenous p53 by adriamycin enhances MDMX cleavage and produces a marked decrease of its intracellular levels, while not affecting the D361A-MDMX mutant. In addition, the D361A-MDMX mutant lacks the ability to inhibit p53 transactivation in respect to wild-type MDMX, suggesting that MDMX caspase cleavage play an important functional role. In conclusion, our results demonstrate that, in analogy to MDM2, MDMX may be subjected to proteolytic modifications that regulate its intracellular levels. Moreover, decrease of MDMX protein levels following p53 activation suggests a p53-dependent regulatory feedback of MDMX function.