Red blood cell distribution width (RDW) - A new nutritional biomarker to assess nutritional risk and response to nutritional therapy?

BACKGROUND & AIMS: Red cell distribution width (RDW) has been proposed as a surrogate marker for acute and chronic diseases and may be influenced by nutritional deficits. We assessed the prognostic value of RDW regarding clinical outcomes and nutritional treatment response among medical inpatients at nutritional risk. METHODS: This is a secondary analysis of EFFORT, a randomized, controlled, prospective, multicenter trial investigating the effects of nutritional support in patients at nutritional risk in eight Swiss hospitals. We examined the association between RDW and mortality in regression analysis. RESULTS: Among 1,244 included patients (median age 75 years, 46.6 % female), high RDW (≥15 %) levels were found in 38 % of patients (n = 473) with a significant association of higher malnutrition risk [OR 1.48 (95%CI 1.1 to 1.98); p = 0.009]. Patients with high RDW had a more than doubling in short-term (30 days) mortality risk [adjusted HR 2.12 (95%CI 1.44 to 3.12); p < 0.001] and a signficant increase in long-term (5 years) mortality risk [adjusted HR 1.73 (95%CI 1.49 to 2.01); p < 0.001]. Among patients with high RDW, nutritional support reduced morality within 30 days [adjusted OR 0.56 (95%CI 0.33 to 0.96); p = 0.035], while the effect of the nutritional intervention in patients with low RDW was markedly smaller. CONCLUSIONS: Among medical patients at nutritional risk, RDW correlated with several nutritional parameters and was a strong prognostic marker for adverse clinical outcomes at short- and long-term, respectively. Patients with high baseline RDW levels also showed a strong benefit from the nutritional intervention. Further research is needed to understand whether monitoring of RDW over time severs as a nutritional biomarker to assess effectiveness of nutritional treatment in the long run. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02517476.

Long-term outcomes in patients with Cushing's disease vs nonfunctioning pituitary adenoma after pituitary surgery: an active-comparator cohort study.

OBJECTIVE: There is increasing evidence that multisystem morbidity in patients with Cushing's disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with nonfunctioning pituitary adenoma (NFPA) after pituitary surgery. DESIGN: Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021. METHODS: Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (ie, myocardial infarction, unstable angina, heart failure, cardiac arrest, and ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence. RESULTS: After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. Cushing's disease presence was associated with a higher incidence rate of the primary endpoint (40.6 vs 15.7 events per 1000 person-years, hazard ratio [HR] 2.75; 95% CI, 1.54-4.90). Cushing's disease patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59-6.71) and a trend for sepsis (HR 3.15; 95% CI, .95-10.40). CONCLUSIONS: Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis.

Nutritional support in hospitalised patients with diabetes and risk for malnutrition: a secondary analysis of an investigator-initiated, Swiss, randomised controlled multicentre trial.

OBJECTIVES: The main objective of this study was to investigate the effects of nutritional support on mortality in hospitalised patients with diabetes and nutritional risk participating in the Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) trial. DESIGN: Secondary analysis of a Swiss-wide multicentre, randomised controlled trial. PARTICIPANTS: Patients with diabetes and risk for malnutrition. INTERVENTIONS: Individualised nutritional support versus usual care. PRIMARY OUTCOME MEASURE: 30-day all-cause mortality. RESULTS: Of the 2028 patients included in the original trial, 445 patients were diagnosed with diabetes and included in this analysis. In terms of efficacy of nutritional therapy, there was a 25% lower risk for mortality in patients with diabetes receiving nutritional support compared with controls (7% vs 10%, adjusted HR 0.75 (95% CI 0.39 to 1.43)), a finding that was not statistically significant but similar to the overall trial effects with no evidence of interaction (p=0.92). Regarding safety of nutritional therapy, there was no increase in diabetes-specific complications associated with nutritional support, particularly there was no increase in risk for hyperglycaemia (adjusted OR 0.97, 95% CI 0.56 to 1.67 p=0.90). CONCLUSION: Patients with diabetes and malnutrition in the hospital setting have a particularly high risk for adverse outcomes and mortality. Individualised nutritional support reduced mortality in this secondary analysis of a randomized trial, but this effect was not significant calling for further large-scale trials in this vhighly ulnerable patient population. TRIAL REGISTRATION NUMBER: NCT02517476.

Confounding Factors in Targeted Degradation of Short-Lived Proteins.

Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but to what extent it influences target protein degradation has not been systematically explored. Using simple mathematical modeling of protein degradation, we find that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a degrader agent which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein-degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required to conclude that a novel agent works as a bona fide targeted protein degrader.