Identification of integrated proteomics and transcriptomics signature of alcohol-associated liver disease using machine learning.

Distinguishing between alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC) remains a diagnostic challenge. In this study, we used machine learning with transcriptomics and proteomics data from liver tissue and peripheral mononuclear blood cells (PBMCs) to classify patients with alcohol-associated liver disease. The conditions in the study were AH, AC, and healthy controls. We processed 98 PBMC RNAseq samples, 55 PBMC proteomic samples, 48 liver RNAseq samples, and 53 liver proteomic samples. First, we built separate classification and feature selection pipelines for transcriptomics and proteomics data. The liver tissue models were validated in independent liver tissue datasets. Next, we built integrated gene and protein expression models that allowed us to identify combined gene-protein biomarker panels. For liver tissue, we attained 90% nested-cross validation accuracy in our dataset and 82% accuracy in the independent validation dataset using transcriptomic data. We attained 100% nested-cross validation accuracy in our dataset and 61% accuracy in the independent validation dataset using proteomic data. For PBMCs, we attained 83% and 89% accuracy with transcriptomic and proteomic data, respectively. The integration of the two data types resulted in improved classification accuracy for PBMCs, but not liver tissue. We also identified the following gene-protein matches within the gene-protein biomarker panels: CLEC4M-CLC4M, GSTA1-GSTA2 for liver tissue and SELENBP1-SBP1 for PBMCs. In this study, machine learning models had high classification accuracy for both transcriptomics and proteomics data, across liver tissue and PBMCs. The integration of transcriptomics and proteomics into a multi-omics model yielded improvement in classification accuracy for the PBMC data. The set of integrated gene-protein biomarkers for PBMCs show promise toward developing a liquid biopsy for alcohol-associated liver disease.

Quantitative imaging biomarkers of coronary plaque morphology: insights from EVAPORATE.

Aims: Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result. Methods and Results: EVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mm3 vs. an increase of 41 mm3, p = 0.008), widening at 18 months (6 mm3 vs. 58 mm3 increase, p = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p < 0.01 (sustained at 18 months), generalizing well to a validation cohort. Conclusion: Plaques in the IPE-treated patients acquired more characteristics of stability. Reliable assessment using histologically validated analysis of individual response is possible at 9 months, with sustained stabilization at 18 months, providing a quantitative basis to elucidate drug mechanism and assess individual patient response.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis.

Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent studies have shown that defective function of hepatocyte nuclear factor 4 alpha (HNF4a) and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein, an integrative analysis of hepatic RNA sequencing and liquid chromatography-tandem mass spectrometry was performed to identify plasma protein signatures for patients with mild and severe AH. Alcohol-related liver disease cirrhosis, nonalcoholic fatty liver disease, and healthy subjects were used as comparator groups. Levels of identified proteins primarily involved in hepatocellular function were decreased in patients with AH, which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified, including thrombin, hepatocyte growth factor α, clusterin, human serum factor H-related protein, and kallistatin, which exhibited large abundance shifts between severe and nonsevere AH. The combination of thrombin and hepatocyte growth factor α discriminated between severe and nonsevere AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.

Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples.

Background & Aims: Liver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples. Methods: We collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools. Results: Utilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes. Conclusions: Our machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases. Lay summary: Distinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.

Solumedrol Treatment for Severe Sepsis in Humans with a Blunted Adrenocorticotropic Hormone-Cortisol Response: A Prospective Randomized Double-Blind Placebo-Controlled Pilot Clinical Trial.

PURPOSE: To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13 µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250 µg of ACTH, and serum cortisol was measured at times 0, 30, and 60 min. Eleven patients failed to increase their cortisol concentration above 19.9 µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1 µg/dL increased to 38 ± 3 µg/dL at 30 min and 40 ± 3 at 60 min. All cortisol responses were <12.9 µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20 mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8 h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P < .05 as significant. RESULTS: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20 mg every 8 h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.

Prevalence of normal coronary arteries by coronary computed tomography angiography (CCTA) in patients with type 2 diabetes mellitus from Semaglutide Treatment on Coronary Plaque Progression (STOP) trial.

INTRODUCTION: Coronary artery disease (CAD) is leading cause of morbidity and mortality among type 2 diabetics (T2DM). METHODS: 140 T2DM will be enrolled in randomized, double blind, placebo controlled Semaglutide Treatment On Coronary Plaque Progression (STOP) trial to determine effect of weekly subcutaneous semaglutide on coronary plaque progression. All participants will undergo Coronary Artery Calcium (CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. A Fisher test, ANOVA and Kruskal Wallis were used. RESULTS: As of May 2020, 87 patients (81%) randomized (mean age 56.4 ± 8.4 yrs. and 62% male) with documented CAD by CCTA. Approximately 20% of screened study population were screen failed due to normal coronaries (n= 14) or HbA1C<7 (n=7). Of interest, 14 persons with diabetes with normal coronaries (no calcification) were significantly more likely to be females (21% vs 62%), have higher glomerular filtration rate (106.5 ± 19.4 vs 89.9 ± 22.6 mL/min/1.73m2; p= 0.006), and younger (53.4 ± 9.0 vs 56.4 ± 8.4 yrs.; p=0.02) than those who were randomized. CONCLUSION: Among T2DM, there is a significant portion who have normal coronary arteries and may have a better prognosis. Excluding these participants from cardiovascular studies may improve power and decrease sample size.

Vitamin A treatment for severe sepsis in humans; a prospective randomized double blind placebo-controlled clinical trial.

PURPOSE: To test the benefits of Vitamin A treatment in patients with sepsis on length of time in ICU, days on ventilator, days on intravenous blood pressure support and 28-day mortality. The trial was prospective, randomized and double-blind. As part of a larger sepsis trial, 63 patients with sepsis were randomized to receive either 100,000 IU of Vitamin A intramuscular or placebo over 7-days. Data analysis was by ANOVA with two tailed test and p < 0.05 as significant. RESULTS: The mean age was 51 ± 2 (mean ± SEM) with 54% female. Groups were well matched with regards to APACHE III score, WBC count, and incidence of bacteremia. In addition, all patients had an ACTH stimulation test using 250 mcg of ACTH IV and serum cortisol was measured at time 0, 30 and 60 min. Baseline cortisol of 24.6 ± 1 mg/dl increased to 41 ± 2 mg/dl at 30 min and 49 ± 2 at 60 min. There was no significant difference between the groups. All cortisol responses were greater than 11.9 mg/dl. Serum Vitamin A level was below normal in 54% of the patients. After randomization, 100,000 IU of Vitamin A daily was given to 32 patients and blinded placebo was given daily to 32 patients for seven days. This was administered as a 1 cc injection of either medication or placebo and was blinded from all but the research pharmacist. The number of days in the ICU was slightly, but not significantly reduced (p = 0.39) by approximately 2 days in the Vitamin A treated patients. The average number of days on blood pressure agents and the day on ventilator were similar. The 28-day mortality rates were similar between the two groups (28 vs 34% placebo vs Vitamin A group). Seven days of high dose intramuscular Vitamin A treatment in patients with sepsis where approximately 50% were vitamin A deficient had no benefit in adults with sepsis.

The durability of oral diabetic medications: Time to A1c baseline and a review of common oral medications used by the primary care provider.

INTRODUCTION: Cost of generic medications has risen more in the past few years than any other time in history. While medical insurance covers much of these costs, health care professionals can better provide medications that have the longest duration of action when compared to placebo-treated controls. This will save health care costs and improve prescribing accuracy. METHODS: Papers in PubMed were identified with keywords placebo. The study must be at least 2 years in length to evaluate the change in A1c over time. The primary endpoint was time to A1c neutrality (return of A1c to baseline at a maximum dose of single oral agent). A medication would be considered at neutrality if the 95% CI crossed baseline. Time to neutrality was averaged for each medication within the class and each summarized for class effect. RESULTS: Effective therapy for the DPP-4 and sulfonylurea classes of medications are 3-4 years as compared to a 5-year time to A1c neutrality for metformin usage. In comparison, the projected time to A1c neutrality was approximately 6-8 years for rosiglitazone and pioglitazone. While only a few studies have been published in the SGLT-2 class of medication, the time to A1c neutrality was also 6-8 years with Canagliflozin and full dosage of Empagliflozin. CONCLUSION: Metformin appears to have a 5-year duration of effect before the A1c returns to baseline. The sulfonylureas and DPP-4 inhibitors class of medications have one of the shortest durability which ranges between 3.3 to 4.4 years. In contrast, the SGLT-2 class of medication and the TZD class of medications has a projected time to A1c neutrality from 6-8 years. Diabetic duration of therapy as compared to placebo should be listed with those medications tested so the provider can choose wisely.

Importance of fasting blood glucose goals in the management of type 2 diabetes mellitus: a review of the literature and a critical appraisal.

Prandial insulin has been essential for the improved management of the type 1 diabetic patient. Interestingly, many studies have evaluated the addition of prandial insulin to the type 2 diabetic patients with improved control. The greatest drop in A1c with the use of various type of prandial insulins have resulted in the decrease of 1.3% in the A1c measurement. Interestingly, none of the published trials with goal of fasting blood glucose (FBG) have ever obtained the goal A1c. Since a drop in FBG of 28.7mg/dl is equal to a 1% drop in A1c, a simple approach to obtain a target A1c would be to focus on the FBG (per ADA: Average Blood Glucose = A1c (%) x 28.7 - 46.7mg/d). However, average blood glucose requires multiple measurements and may be less accurate then using just a FBG. Since prandial insulin clinical trials have only demonstrated a drop in A1c by 0.3-1.3% the use of only a FBG to help patients get to goal may be easier to teach and to obtain. It might save time and money. Our hypothesis is that if patient obtain a FBG <100 mg/dl for 2-3 months then 70% will be at an A1c goal <7.0%. After a few months of good fasting glucose control the provider can use this equation (FBG+80)/30 to estimate A1c. For example, a FBG of 130mg/dl would be (130 + 80)/30 = 7.0%; or a FBG of 190 would be (190+80)/30 =eA1c 9% (estimate of A1c). While type 1 diabetes has a very complex daily glucose pattern, the approach to type 2 diabetics on insulin could become simplified.

Weight loss and diabetes are new risk factors for the development of invasive aspergillosis infection in non-immunocompromized humans.

Well-established risk factors for aspergillosis include HIV, cancer, recent corticosteroid (prednisone) therapy, chemotherapy, or thoracic surgery. Non-established risk factors may include weight loss and a history of diabetes. Twenty-three patients without the classical risk factors for IA were identified retrospectively at Harbor UCLA Medical Center by discharge diagnosis over a 20 year period (1992-2012). None of the well-known risk factors are for Invasive Apergillious (IA). A history of weight loss was seen in 66% of the patients with IA (15 of 23). The weight loss ranged from 3.3 lbs to 43 lbs. In patients with weight loss the average loss was 22±3 lbs (mean±SEM). In this small group of patients with IA, diabetes was seen in 8 of the 23 (34%), which is significantly higher than the 19% incidence of diabetes seen in 100 patients with severe sepsis (p<0.05). Likewise, the 34% incidence of diabetes was higher than the 21% incidence reported in immunocompromised patients with invasive aspergillus (IA) infection (p<0.05). A reduced serum albumin concentration was seen in 33% of the study patients, which was less common than the 87% incidence seen in patients with severe sepsis or candidaemia (54%). Seventeen of the 23 patients had pulmonary involvement. While no one had a well-established risk factor for aspergillious, four patients had alcoholism as a potential risk factor. Eleven of the 23 (48%) died during the hospital stay despite antifungal therapy. Immunocompromised patients are known to have a mortality rate of approximately 45% for pulmonary or disseminated disease. CONCLUSION: The incidence of diabetes was greater than seen in immunocompromised patients and may be considered an additional risk factor for the development of aspergillois infection. In addition, a history of weight loss should increase the suspicion for the diagnosis of IA in otherwise a non-immunocompromised patient. Early recognition and treatment of aspergillosis in the non-immunocompromised patient may improve outcome. Weight loss and diabetes should be added to the list of well-known risk factors for invasive aspergillosis and its high mortality rate.

Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature.

Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 µg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient.

Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.

BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literature.

BACKGROUND: Higher muscle mass is associated with better outcomes and longevity in patients with chronic disease states. Imaging studies such as dual-energy X-ray absorptiometry (DEXA) are among the gold standard methods for assessing body fat and lean body mass (LBM), approximately half of which is comprised of skeletal muscle mass. Elaborate imaging devices, however, are not commonly available in routine clinical practice and therefore easily accessible and cost-effective, but reliable muscle mass biomarkers are needed. One such marker is serum creatinine, derived from muscle-based creatine, which is inexpensive and ubiquitously available, and it can serve as a biomarker of skeletal muscle mass in human subjects. METHODS AND RESULTS: In 118 hemodialysis patients, we found that the 3-month averaged serum creatinine concentration correlated well with DEXA-measured LBM. The recent literature regarding serum creatinine as a surrogate of muscle mass is summarized, as is the literature concerning the use of other measures of muscle mass, such as plasma gelsolin and actin, and urinary creatinine excretion. We have also reviewed the role of dietary meat intake in serum creatinine variability along with several biomarkers of dietary meat intake (creatine, carnitine, carnosine, ophidine, anserine, 3-methyl-L-histidine and 1-methylhistidine). CONCLUSION: In summary, none of these biomarkers was studied in CKD patients. We advance the hypothesis that in both health and disease, under steady state, serum creatinine can serve as a reliable muscle mass biomarker if appropriate adjustment for full or residual kidney function and dietary meat intake is undertaken.

Identification of noncalcified plaque in young persons with diabetes: an opportunity for early primary prevention of coronary artery disease identified with low-dose coronary computed tomographic angiography.

PURPOSE: Coronary computed tomographic angiography (CTA) is a valuable tool for assessing coronary artery disease (CAD). Although statin use is widely recommended for persons with diabetes older than age 40, little is known about the presence and severity of CAD in younger patients with diabetes mellitus (DM). We evaluated coronary artery calcium (CAC) and coronary CTA in young persons with both DM1 and DM2 in an attempt to detect the earliest objective evidence of arteriosclerosis eligible for primary prevention. METHODS AND MATERIALS: We prospectively enrolled 40 persons with DM (25 type 1 and 15 type 2) between the ages of 19 and 35 presenting with diabetes for 5 years or longer. All patients underwent coronary CTA and CAC scans to evaluate for early atherosclerotic disease. Each plaque in the coronary artery was classified as noncalcified or calcified-mixed. We also evaluated all segments with stenosis, dividing them into mild (<50%), moderate (50-70%), and severe (>70%). RESULTS: The average age of the DM1 subjects were 26 ± 4 (SD) years and 30 ± 4 years for DM2 patients (P < .01), with duration of diabetes of 8 ± 5 years and average HbA1c% of 8.7 ± 1.6 (norm = 4.6-6.2). Abnormal scans were present in 57.5%, noncalcified in 35% and calcified-mixed plaque in 22.5%. Persons with DM2 had a higher prevalence of positive coronary CTA scans than DM1: 80% versus 44% (P < .03) and more positive CAC scores 53% versus 4%, (P < .01). The total segment score of 2.1 ± 3.4 (P < .01) and total plaque score 1.9 ± 2.8 (P < .01) were highly correlated to each other. Plaque was almost uniformly absent below age 25, and became increasingly common in individuals over the age of 25 years for both groups. The average radiation exposure was 2.5 ± 1.3 mSv. CONCLUSION: Our study verifies that early CAD can be diagnosed with coronary CTA and minimal radiation exposure in young adults with DM. A negative CAC score was not sufficient to exclude early CAD as we observed a preponderance of noncalcified plaque in this cohort. Coronary CTA in young DM patients older than age 25 may provide earlier identification of disease than does a CAC because only noncalcified plaque is frequently present. Coronary CTA provides an opportunity to consider initiation of earlier primary CAD prevention rather than waiting for the age of 40 as currently recommended by the American Diabetes Association guidelines.

Diabetes patients and non-diabetic patients intensive care unit and hospital mortality risks associated with sepsis.

AIM: To compare mortality risks associated with known diabetic patients to hyperglycemic non-diabetic patients. METHODS: PubMed data base was searched for patients with sepsis, bacteremia, mortality and diabetes. Articles that also identified new onset hyperglycemia (NOH) (fasting blood glucose > 125 mg/dL or random blood glucose > 199 mg/dL) were identified and reviewed. Nine studies were evaluated with regards to hyperglycemia and hospital mortality and five of the nine were summarized with regards to intensive care unit (ICU) mortality. RESULTS: Historically hyperglycemia has been believed to be equally harmful in known diabetic patients and non-diabetics patients admitted to the hospital. Unexpectedly, having a history of diabetes when admitted to the hospital was associated with a reduced risk of hospital mortality. Approximately 17% of patients admitted to hospital have NOH and 24% have diabetes mellitus. Hospital mortality was significantly increased in all nine studies of patients with NOH as compared to known diabetic patients (26.7% ± 3.4% vs 12.5% ± 3.4%, P < 0.05; analysis of variance). Unadjusted ICU mortality was evaluated in five studies and was more than doubled for those patients with NOH as compared to known diabetic patients (25.3% ± 3.3% vs 12.8% ± 2.6%, P < 0.05) despite having similar blood glucose concentrations. Most importantly, having NOH was associated with an increased ICU and a 2.7-fold increase in hospital mortality when compared to hyperglycemic diabetic patients. The mortality benefit of being diabetic is unclear but may have to do with adaptation to hyperglycemia over time. Having a history of diabetes mellitus and prior episodes of hyperglycemia may provide time for the immune system to adapt to hyperglycemia and result in a reduced mortality risk. Understanding why diabetic patients have a lower than expected hospital mortality rate even with bacteremia or acute respiratory distress syndrome needs further study. CONCLUSION: Having hyperglycemia without a history of previous diabetes mellitus is a major independent risk factor for ICU and hospital mortality.