Omega-3 Fatty Acids and Markers of Thrombosis in Patients with Atrial Fibrillation.

Omega-3 fatty acids (n-3 FAs) are associated with a lower risk of ischemic stroke in patients with atrial fibrillation (AF). Antithrombotic mechanisms may in part explain this observation. Therefore, we examined the association of n-3 FAs with D-dimer and beta-thromboglobulin (BTG), markers for activated coagulation and platelets, respectively. The n-3 FAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were determined via gas chromatography in the whole blood of 2373 patients with AF from the Swiss Atrial Fibrillation cohort study (ClinicalTrials.gov Identifier: NCT02105844). In a cross-sectional analysis, we examined the association of total n-3 FAs (EPA + DHA + DPA + ALA) and the association of individual fatty acids with D-dimer in patients with detectable D-dimer values (n = 1096) as well as with BTG (n = 2371) using multiple linear regression models adjusted for confounders. Median D-dimer and BTG levels were 0.340 ug/mL and 448 ng/mL, respectively. Higher total n-3 FAs correlated with lower D-dimer levels (coefficient 0.94, 95% confidence interval (Cl) 0.90-0.98, p = 0.004) and lower BTG levels (coefficient 0.97, Cl 0.95-0.99, p = 0.003). Likewise, the individual n-3 FAs EPA, DHA, DPA and ALA showed an inverse association with D-dimer. Higher levels of DHA, DPA and ALA correlated with lower BTG levels, whereas EPA showed a positive association with BTG. In patients with AF, higher levels of n-3 FAs were associated with lower levels of D-dimer and BTG, markers for activated coagulation and platelets, respectively. These findings suggest that n-3 FAs may exert antithrombotic properties in patients with AF.

Association of CT-based diagnosis of sarcopenia with prognosis and treatment response in patients at risk of malnutrition - A secondary analysis of the Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) trial.

BACKGROUND & AIM: CT-derived measures of muscle mass may help to identify patients with sarcopenia. We investigated the prognostic significance of CT-derived sarcopenia and muscle attenuation with nutritional markers, clinical outcomes and response to nutritional support in medical in-patients at nutritional risk. METHOD: Within this secondary analysis of the randomized-controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) comparing individualized nutritional support with usual care nutrition in medical inpatients, we investigated associations of CT-based sarcopenia and muscle attenuation at the level L3 with different nutritional and clinical outcomes, and the response to the nutritional intervention. The primary composite endpoint was adverse clinical outcome within 30 days of hospital admission. RESULTS: We included 573 of 2028 EFFORT patients with available CT scans, of which 68.4% met the CT-based definition of sarcopenia and 72.9% had low muscle attenuation. In multivariate analysis, low skeletal muscle index was associated with higher nutritional risk (coefficient per NRS class -0.94 (95%CI -1.87 to -0.01) p = 0.049) and higher risk for adverse clinical outcomes (adjusted odds ratio 1.59 (95% CI 1.06 to 2.38), p = 0.024). Low muscle attenuation was also associated with adverse clinical outcome (adjusted odds ratio 1.67 (95%CI 1.08 to 2.58), p = 0.02). Nutritional support tended to be more effective in reducing mortality in non-sarcopenic patients compared to patients with CT-based sarcopenia (p for interaction 0.058). CONCLUSIONS: Within a population of medical patients at nutritional risk, CT-based sarcopenia and muscle attenuation were associated with several nutritional parameters and predicted adverse clinical outcomes. Information from CT scans, thus may help to better characterize these patients, and may be helpful in guiding therapeutic interventions.

Validation of modified GLIM criteria to predict adverse clinical outcome and response to nutritional treatment: A secondary analysis of a randomized clinical trial.

BACKGROUND & AIMS: The Global Leadership Initiative on Malnutrition (GLIM) recently suggested specific criteria to standardize the diagnosis of malnutrition. There is need for validation of these criteria regarding response to nutrition treatment. Our aim was to validate modified GLIM (mGLIM) criteria among medical inpatients at risk of disease related malnutrition for prediction of outcome and response to nutritional therapy. METHODS: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a multicenter randomized controlled trial conducted between April 2014 and February 2018. Adult medical inpatients at nutritional risk (Nutrition Risk Score 2002 ≥ 3 points) were randomly assigned to receive nutritional therapy according to an algorithm based on individualized nutritional requirements (intervention group) or standard hospital food (control group). We included all participants with available information regarding mGLIM criteria. The primary outcome was adverse clinical outcome, which was a composite of 30-day all-cause mortality, ICU-admission, rehospitalization rate, major complications and decline in functional status. RESULTS: Of 1917 eligible participants at nutritional risk, 1181 (61.6%) met the diagnosis of malnutrition based on mGLIM criteria. The incidence of adverse clinical outcome was significantly higher in mGLIM-positive participants compared with mGLIM-negative participants [330/1181 (27.9%) versus 140/736 (19.0%); multivariable adjusted odds ratio [OR] 1.53; 95% CI 1.22-1.93; p < 0.001]. Regarding the effect of nutritional therapy, the reduction in adverse clinical outcomes was higher in mGLIM-positive participants [180/581 (31.0%) vs. 150/600 (25.0%), OR 0.69; 95% CI 0.53-0.9, p = 0.007], compared with mGLIM-negative participants [75/379 (19.8%) versus 65/357 (18.2%), OR 0.95; 95% CI 0.65-1.40, p = 0.797], a finding that was, however, not significant in interaction analysis (p for interaction = 0.217). CONCLUSION: Data from this secondary analysis of a multicenter randomized trial involving medical inpatients at nutritional risk validate the strong prognostic value of mGLIM criteria regarding adverse clinical outcomes and other long-term outcomes. However, further research is needed to improve the ability of GLIM criteria to predict therapeutic response to nutritional interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02517476.

Admission serum albumin concentrations and response to nutritional therapy in hospitalised patients at malnutrition risk: Secondary analysis of a randomised clinical trial.

BACKGROUND: Historically, admission serum albumin concentrations have been considered useful biochemical markers for nutrition assessment. However, there is a lack of randomised trial data investigating whether low albumin concentrations are helpful for identifying patients benefitting from nutritional support. METHODS: This study was a secondary analysis of the EFFORT trial, a Swiss-wide multicentre, randomised controlled trial comparing individualised nutritional support with usual care nutrition in medical inpatients from April 1, 2014, to February 1, 2018. 1389 of 2028 patients at nutritional risk with available albumin concentrations on admission were included. The primary endpoint was all-cause mortality within 30 and 180 days. Patients were stratified into groups of low or normal albumin based on the albumin cut-off of 30 g/L. ClinicalTrials.gov number, NCT02517476. FINDINGS: 1389 patients (mean age, 73.1 (SD 3.5) years; 747 (53.8%) men) were included and 676 (48.7%) had low serum albumin concentrations at admission (<30 g/L). Mortality at 180 days was significantly increased in the low albumin group compared with patients with normal albumin concentrations (219/676 (32.4%) vs. 162/713 (22.7%), fully adjusted HR 1.4, 95%CI 1.11 to 1.77, p = 0.005]. Effects of nutritional support on 30-day mortality were similar for patients with low compared to patients with normal albumin concentrations (HR 0.68, 95%CI 0.44 to 1.05 vs. HR 0.70, 95%CI 0.41 to 1.20), with no evidence for a subgroup effect (p for interaction=0.97). INTERPRETATION: Based on this secondary analysis of a randomised trial, low admission serum albumin concentrations in hospitalised, non-critically ill, medical patients at nutritional risk had prognostic implications and indicated higher mortality risk but were not helpful in selecting patients for nutritional interventions. FUNDING: The Swiss National Science Foundation (SNSF) (PP00P3_150531) and the Research Council of the Kantonsspital Aarau (1410.000.058 and 1410.000.044) provided funding for the EFFORT trial.

Vitamin D oral intermittent treatment (DO IT) study, a randomized clinical trial with individual loading regimen.

Comparison of several regimens of oral vitamin D including an individually calculated loading regimen with the aim of achieving serum values > 75 nmol/l. Interventional, randomized, 3-arm study in vitamin D-deficient outpatients. Participants were allocated to supplementation of 24,000 IU vitamin D monthly over three months, using either a monthly drinking solution (Vi-De 3) or capsule (D3 VitaCaps), or an individualized loading regimen with the capsules taken weekly. For the loading regimen, the cumulative dose was calculated according to baseline 25-hydroxy-vitamin D (25(OH)D) serum value and body weight. Main inclusion criteria were age ≥ 18 years and 25(OH)D serum concentration < 50 nmol/l. The primary outcome was 25(OH)D serum concentration one week after treatment termination. Secondary endpoints were patient's preferences and adverse events. Full datasets were obtained from 52 patients. Mean 25(OH)D values were statistically significant higher after a loading regimen compared to a monthly administration of 24,000 IU vitamin D (76.4 ± 15.8 vs 61.4 ± 10.8 nmol/l; p < 0.01). All patients treated with the loading regimen reached sufficient 25(OH)D values > 50 nmol/l. Serum 25(OH)D values > 75 nmol/l were observed more frequently in patients taking the loading regimen (47% vs 11% drinking solution vs 12% capsules). Vitamin D-related adverse effects did not occur in any treatment groups. Capsules were preferred by 88.5% of the patients. Compared to treatments with monthly intake of 24,000 IU vitamin D, the intake of an individually calculated weekly loading regimen was able to raise serum concentrations > 50 nmol/l in all cases within a safe range.

Value of handgrip strength to predict clinical outcomes and therapeutic response in malnourished medical inpatients: Secondary analysis of a randomized controlled trial.

BACKGROUND: Disease-related malnutrition is associated with loss of muscle mass and impaired functional status. Handgrip strength (HGS) has been proposed as an easy-to-use tool to assess muscle strength in clinical practice. OBJECTIVES: We investigated the prognostic implications of HGS in patients at nutritional risk with regard to clinical outcomes and response to nutritional support. METHODS: This was a secondary analysis of the randomized controlled, multicenter, Effect of Early Nutritional Support on Frailty, Functional Outcome, and Recovery of Malnourished Medical Inpatients Trial, which compared the effects of individualized nutritional support with usual hospital food in medical inpatients at nutritional risk. Our primary endpoint was 30-d all-cause mortality. The association between sex-specific HGS and clinical outcomes was investigated using multivariable regression analyses, adjusted for randomization, age, weight, height, nutritional risk, admission diagnosis, comorbidities, interaction terms, and study center. We used interaction terms to investigate possible effect modification regarding the nutritional support intervention. RESULTS: Mean ± SD HGS in the 1809 patients with available handgrip measurement was 17.0 ± 7.1 kg for females and 28.9 ± 11.3 kg for males. Each decrease of 10 kg in HGS was associated with increased risk of 30-d mortality (female: adjusted OR: 2.11; 95% CI: 1.23, 3.62, P = 0.007; male: adjusted OR: 1.44; 95% CI: 1.07, 1.93, P = 0.015) and 180-d mortality (female: adjusted OR: 1.45; 95% CI: 1.0, 2.10, P = 0.048; male: adjusted OR: 1.55; 95% CI: 1.28, 1.89, P < 0.001). Individualized nutritional support was most effective in reducing mortality in patients with low HGS (adjusted OR: 0.29; 95% CI: 0.10, 0.82 in patients in the ≤10th percentile compared with OR: 0.98; 95% CI: 0.66, 1.48 in patients in the >10th percentile; P for interaction = 0.026). CONCLUSIONS: In medical inpatients at nutritional risk, HGS provided significant prognostic information about expected mortality and complication risks and helps to identify which patients benefit most from nutritional support. HGS may thus improve individualization of nutritional therapy.This trial was registered at clinicaltrials.gov as NCT02517476.

Oral intermittent vitamin D substitution: influence of pharmaceutical form and dosage frequency on medication adherence: a randomized clinical trial.

BACKGROUND: To assess adherence to and preference for vitamin D substitution with different pharmaceutical forms and frequencies of administration. METHODS: A focus group of stakeholders aimed at preparing the design of an interventional, randomized, cross-over study with 2 × 2 groups obtaining monthly or weekly vitamin D products in liquid or solid form for 3 months each. Dosage corresponds to cumulated amount of recommended 800 IU daily (5.600 IU weekly / 24.000 IU monthly). Main inclusion criteria were a vitamin D serum value < 50 nmol/l and age ≥ 18 years. Primary endpoint was adherence, secondary endpoints were preferences and vitamin D serum levels. RESULTS: The focus group reached consensus for preference of a monthly administration of solid forms to adults. Full datasets were obtained from 97 participants. Adherence was significantly higher with monthly (79.5-100.0%) than weekly (66.4-98.1%) administration. Vitamin D levels increased significantly (p < 0.001) in all participants. An optimal value of > 75 nmol/l was achieved by 32% after 3 months and by 50% after 6 months. Preferred formulation was solid form (tablets, capsules) for 71% of participants, and preferred dosage frequency was monthly for 39% of participants. CONCLUSIONS: Monthly oral vitamin D in solid form lead to the highest adherence, and is preferred by the participants. However, only one third of study participants achieved values in the optimal range of > 75 nmol/l cholecalciferol using weekly or monthly administration providing an average daily cholecalciferol dose of 800 IU. TRIAL REGISTRATION: NCT03121593 | SNCTP000002251 . Registered 30. May 2017,. Prospectively registered.

Vitamin D deficiency is highly prevalent in malnourished inpatients and associated with higher mortality: A prospective cohort study.

The impact of vitamin D deficiency on the recovery of patients with malnutrition remains undefined. Our aim was to study the prevalence of vitamin D deficiency in a well-characterized cohort of patients with malnutrition and its association with outcomes.Within this secondary analysis of a randomized controlled trial, we examined the association of vitamin D deficiency and adverse clinical outcomes over a follow-up of 180 days in hospitalized patients at risk for malnutrition. We measured 25-hydroxyvitamin D levels upon admission and defined Vitamin D deficiency when levels were <50nmol/l. The primary endpoint was 180-day mortality.The prevalence of vitamin D deficiency in our cohort of 828 patients was 58.2% (n = 482). Patients with vitamin D deficiency had increased 180-day mortality rates from 23.1% to 29.9% (odds ratio 1.42, 95% confidence interval [CI] 1.03-1.94, P = .03). When adjusting the analysis for demographics, comorbidities, and randomization, this association remained significant for the subgroup of patients not receiving vitamin D treatment (adjusted odds ratio 1.63, 95% CI 1.01-2.62, P = .04). There was no significantly lower risk for mortality in the subgroup of vitamin D deficient patients receiving vitamin D treatment compared to not receiving treatment (adjusted odds ratio 0.74, 95% CI 0.48-1.13, P = .15).Vitamin D deficiency is highly prevalent in the population of malnourished inpatients and is negatively associated with long-term mortality particularly when patients are not receiving vitamin D treatment. Our findings suggest that malnourished patients might benefit from vitamin D screening and treatment in case of deficiency.

Expression of regulated secretory proteins is sufficient to generate granule-like structures in constitutively secreting cells.

The formation of secretory granules and regulated secretion are generally assumed to occur only in specialized endocrine, neuronal, or exocrine cells. We discovered that regulated secretory proteins such as the hormone precursors pro-vasopressin, pro-oxytocin, and pro-opiomelanocortin, as well as the granins secretogranin II and chromogranin B but not the constitutive secretory protein alpha(1)-protease inhibitor, accumulate in granular structures at the Golgi and in the cell periphery in transfected COS-1 fibroblast cells. The accumulations were observed in 30-70% of the transfected cells expressing the pro-hormones and for virtually all of the cells expressing the granins. Similar structures were also generated in other cell lines believed to be lacking a regulated secretory pathway. The accumulations resembled secretory granules morphologically in immunofluorescence and electron microscopy. They were devoid of markers of the endoplasmic reticulum, endosomes, and lysosomes but in part stained positive for the trans-Golgi network marker TGN46, consistent with their formation at the trans-Golgi network. When different regulated proteins were coexpressed, they were frequently found in the same granules, whereas alpha(1)-protease inhibitor could not be detected in accumulations formed by secretogranin II, demonstrating segregation of regulated from constitutive secretory proteins. In pulse-chase experiments, significant intracellular storage of secretogranin II and chromogranin B was observed and secretion of retained secretogranin II was stimulated with the calcium ionophore A23187. The results suggest that expression of regulated cargo proteins is sufficient to generate structures that resemble secretory granules in the background of constitutively secreting cells, supporting earlier proposals on the mechanism of granule formation.