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LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.
Rader, DJ, Maratos-Flier, E, Nguyen, A, Hom, D, Ferriere, M, Li, Y, Kompa, J, Martic, M, Hinder, M, Basson, CT, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e57-e70
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Abstract
PURPOSE To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER NCT03466203.
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Associations Between Preoperative Biomarkers and Cardiac Surgery-Associated Acute Kidney Injury in Elderly Patients: A Cohort Study.
Verwijmeren, L, Bosma, M, Vernooij, LM, Linde, EM, Dijkstra, IM, Daeter, EJ, Van Dongen, EPA, Van Klei, WA, Noordzij, PG
Anesthesia and analgesia. 2021;(3):570-577
Abstract
BACKGROUND Acute kidney injury (AKI) is associated with mortality after cardiac surgery. Novel risk factors may improve identification of patients at risk for renal injury. The authors evaluated the association between preoperative biomarkers that reflect cardiac, inflammatory, renal, and metabolic disorders and cardiac surgery-associated AKI (CSA-AKI) in elderly patients. METHODS This was a secondary analysis of the 2-center prospective cohort study "Anesthesia Geriatric Evaluation." Twelve biomarkers were determined preoperatively in 539 patients. Primary outcome was CSA-AKI. The association between biomarkers and CSA-AKI was investigated with multivariable logistic regression analysis. Secondary outcomes were 1-year mortality and patient-reported disability and were assessed with relative risks (RR) between patients with and without CSA-AKI. RESULTS CSA-AKI occurred in 88 (16.3%) patients and was associated with increased risk of mortality (RR, 6.70 [95% confidence interval {CI}, 3.38-13.30]) and disability (RR, 2.13 [95% CI, 1.53-2.95]). Preoperative concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitive C-reactive protein (hs-CRP), hemoglobin, and magnesium had the strongest association with CSA-AKI. Identification of patients with CSA-AKI improved when a biomarker panel was used (area under the curve [AUC] 0.75 [95% CI, 0.69-0.80]) compared to when only clinical risk factors were used (European System for Cardiac Operative Risk Evaluation [EuroSCORE II] AUC 0.67 [95% CI, 0.62-0.73]). CONCLUSIONS Preoperative cardiac, inflammatory, renal, and metabolic biomarkers are associated with CSA-AKI and may improve identification of patients at risk.
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Nutritional markers and proteome in patients undergoing treatment for pulmonary tuberculosis differ by geographic region.
Jarsberg, LG, Kedia, K, Wendler, J, Wright, AT, Piehowski, PD, Gritsenko, MA, Shi, T, Lewinsohn, DM, Sigal, GB, Weiner, MH, et al
PloS one. 2021;(5):e0250586
Abstract
INTRODUCTION Contemporary phase 2 TB disease treatment clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for optimizing curative treatments. METHODS We characterized clinical features and the serum proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host serum protein expression in clinical trial participants enrolled in African and Non-African regions. Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29 (NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). RESULTS After a peptide level proteome analysis utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS) and subsequent statistical analysis, a total of 183 core proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathways. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways. CONCLUSIONS We have identified differentially expressed nutrition and lipid pathway proteins by geographic region in TB patients undergoing treatment for pulmonary tuberculosis, which appear to be associated with differential treatment responses. Future TB clinical trials should collect expanded measures of nutritional status and further evaluate the relationship between nutrition and microbiologic treatment response.
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Prospective observational study of nutritional/immunologic indices as predictive biomarkers for the response to anti-PD-1 drugs in non-small cell lung cancer (ICI-PREDICT study).
Takamori, S, Ohba, T, Shimokawa, M, Matsubara, T, Haratake, N, Miura, N, Toyozawa, R, Yamaguchi, M, Seto, T, Takenoyama, M
PloS one. 2021;(10):e0258616
Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025.
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Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.
Sen, T, Li, J, Neuen, BL, Neal, B, Arnott, C, Parikh, CR, Coca, SG, Perkovic, V, Mahaffey, KW, Yavin, Y, et al
Diabetologia. 2021;(10):2147-2158
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AIMS/HYPOTHESIS Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). METHODS Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. RESULTS In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. CONCLUSIONS/INTERPRETATION Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.
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Serological Biomarkers and Diversion Colitis: Changes after Stimulation with Probiotics.
Rodríguez-Padilla, Á, Morales-Martín, G, Pérez-Quintero, R, Gómez-Salgado, J, Ruiz-Frutos, C
Biomolecules. 2021;(5)
Abstract
Diversion colitis is a non-specific inflammation of a defunctionalised segment of the colon after a temporary stoma has been performed. This inflammation is associated with an alteration of certain inflammatory serum markers. The aims of this study were, firstly, to evaluate the modification of inflammatory biomarkers after stimulation with probiotics prior to closure of the protective ileostomy. Secondly, to identify if a relationship could be established between the severity of diversion colitis and the alteration of inflammatory biomarkers in the blood. A prospective, randomized, double-blind, controlled study was conducted. Patients who underwent surgery for colorectal carcinoma with protective ileostomy between January 2017 and December 2018 were included, pending reconstructive surgery and with diversion colitis as diagnosis. The sample was randomly divided into a group stimulated with probiotics (SG) (n = 34) and a control group (CG) (n = 35). Histological and endoscopic changes were evaluated after stimulation, after restorative surgery and during the short-term follow-up after surgery, including the correlation with pro-inflammatory biomarkers in blood. As main findings, a significant decrease in C-reactive protein (CRP), Neutrophil/lymphocyte ratio (NLR ratio), and monocyte/lymphocyte ratio (LMR ratio) was observed in the SG versus the CG with a p < 0.001. A significant increase in transferrin values and in the platelet/lymphocyte ratio (PLR) was observed in the SG versus CG after stimulation with probiotics with a p < 0.001. A normalisation of CRP and transferrin levels was observed in the third month of follow-up after closure ileostomy, and NLR, LMR and PLR ratios were equal in both groups. Decreased modified Glasgow prognostic score was found in SG compared to CG after probiotic stimulation (p < 0.001). The endoscopic and histological severity of diversion colitis is associated with a greater alteration of blood inflammatory biomarkers. The stimulation with probiotics prior to reconstructive surgery promotes an early normalization of these parameters.
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Randomized trial of an intensified, multifactorial intervention in patients with advanced-stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan).
Shikata, K, Haneda, M, Ninomiya, T, Koya, D, Suzuki, Y, Suzuki, D, Ishida, H, Akai, H, Tomino, Y, Uzu, T, et al
Journal of diabetes investigation. 2021;(2):207-216
Abstract
AIMS/INTRODUCTION We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced-stage diabetic kidney disease (DKD). MATERIALS AND METHODS The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) is a multicenter, open-label, randomized controlled trial with a 5-year follow-up period. We randomly assigned 164 patients with advanced-stage diabetic kidney disease (urinary albumin-to-creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2-2.5 mg/dL in men and 1.0-2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end-stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention-to-treat population. RESULTS The IT tended to reduce the risk of primary end-points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43-1.11; P = 0.13). Meanwhile, the decrease in serum low-density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05-1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28-0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups. CONCLUSIONS The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow-up study might show the effect of IT in patients with advanced diabetic kidney disease.
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Effect of a Multifactorial Intervention on Fracture in Patients With Type 2 Diabetes: Subanalysis of the J-DOIT3 Study.
Sasako, T, Ueki, K, Miyake, K, Okazaki, Y, Takeuchi, Y, Ohashi, Y, Noda, M, Kadowaki, T
The Journal of clinical endocrinology and metabolism. 2021;(5):e2116-e2128
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AIMS: To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes. METHODS Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c < 6.9%, blood pressure <130/80 mm Hg, LDL-cholesterol <120mg/dL) or intensive therapy (HbA1c < 6.2%, blood pressure <120/75 mm Hg, LDL-cholesterol <80mg/dL) (ClinicalTrials.gov registration no. NCT00300976). RESULTS The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P = 0.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P = 0.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P < 0.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P = 0.025). CONCLUSIONS Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women.
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Effects of Chair-Based, Low-Load Elastic Band Resistance Training on Functional Fitness and Metabolic Biomarkers in Older Women.
Stojanović, MDM, Mikić, MJ, Milošević, Z, Vuković, J, Jezdimirović, T, Vučetić, V
Journal of sports science & medicine. 2021;(1):133-141
Abstract
Strength training can improve myriad health parameters in elderly cohorts. Although potentially more appropriate for the elderly, low-load resistance training protocols have been less investigated. We aimed to examine the effects of 12 weeks of chair-based, low-load resistance training with elastic band (EBT) on functional fitness and metabolic biomarkers in older women. One hundred sixty-eight women were allocated randomly to an elastic band resistance training (EBT, n = 86, 75.7 ± 8.9 years, 71.3 ± 12.2 kg) or a control group (CON, n = 82, 74.5 ± 8.2years, 70.6 ± 12.0 kg). RT protocol consisted of periodized chair-based, low-load whole-body resistance exercises (2 sets, 12-15 repetitions, 40-60% of one repetition maximum-1RM) using an elastic band, twice weekly for 12 weeks. The resistance training program was generally designed to maintain internal load over time, provided with increasing intensity using various elastic bands (Thera-Band). Functional fitness (30-s Chair Stand,30-s Arm Curl, 2-min Step Test, Chair Sit-and-Reach, Back Scratch, 8-Foot Up-and-Go, Handgrip Strength) and metabolic markers (Fasting blood glucose, triglycerides, total cholesterol, high (HDL) and low (LDL) density lipoprotein) were measured before and after the training period. To detect pre/post intervention changes and between group- differences 2x2 repeated measures ANOVA was applied. Significant improvements over time for all fitness variables for EBT comparing to CON were obtained (F = 12.78, p < 0.05 for 30-s Chair Stand; F = 14.04, p < 0.05 for 30-s Arm Curl; F = 5.18, p < 0.05 for 2-min Step Test; F = 10.90, p < 0.05 for Chair Sit-and-Reach; F = 16.57, p < 0.05 for Back Scratch; F = 11.79, p < 0.05 for 8-foot Up-and-Go; and F = 29.25, p < 0.05 for Handgrip Strength). In addition, significant improvements over time for all but one (triglycerides) biomarkers for EBT comparing to CON were obtained (F = 7.30, p < 0.05 for blood sugar levels; F = 13.36, p < 0.05 for total cholesterol; F = 8.61, p < 0.05 for HDL; and F = 11.53, p < 0.05 for LDL). Furthermore, the participants' adherence to training sessions of over 90% was reported. In conclusion, 12 weeks of EBT is safe and beneficial for improving health-related fitness and metabolic biomarkers in older women and seems to be viable model to ensure a high training adherence rate.
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Circulating 27-hydroxycholesterol and Risk of Colorectal Adenomas and Serrated Polyps.
Passarelli, MN, Thompson, BM, McDonald, JG, Snover, DC, Palys, TJ, Rees, JR, Barry, EL, Baron, JA
Cancer prevention research (Philadelphia, Pa.). 2021;(4):479-488
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Abstract
The oxysterol 27-hydroxycholesterol (27-OHC) is an endogenous selective estrogen receptor modulator implicated in breast cancer etiology. It is unknown whether circulating 27-OHC is associated with colorectal neoplasia risk. Circulating 27-OHC was measured using LC/MS in fasting plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed randomized clinical trial. Participants were between 45 and 75 years old, recently diagnosed with ≥1 colorectal adenoma, and followed for new colorectal polyps during colonoscopic surveillance. Adjusted risk ratios (RR) with 95% confidence intervals (CI) of new colorectal polyps were estimated for quartiles of circulating 27-OHC using log-linear regression for repeated outcomes. Polyp phenotypes included any adenomas, advanced adenomas, hyperplastic polyps, and sessile serrated adenomas/polyps. Circulating 27-OHC was measured at baseline for 1,246 participants. Compared with participants with circulating 27-OHC below the first quartile (<138 ng/mL), those with circulating 27-OHC at or above the fourth quartile (≥201 ng/mL) had 24% higher risk of adenomas (RR, 1.24; 95% CI, 1.05-1.47) and 89% higher risk of advanced adenomas (RR, 1.89; 95% CI, 1.17-3.06). Stronger associations were observed among participants with advanced adenomas at baseline. Circulating 27-OHC was not associated with risk of hyperplastic polyps (RR, 0.90; 95% CI, 0.66-1.22) or sessile serrated adenomas/polyps (RR, 1.02; 95% CI, 0.50-2.07). Circulating 27-OHC may be a risk factor for colorectal adenomas but not serrated polyps. PREVENTION RELEVANCE This study found that plasma concentration of 27-hydroxycholesterol, a metabolite of cholesterol that regulates lipid metabolism and acts as a selective estrogen receptor modulator, is associated with the risk of developing precursor lesions for colorectal cancer.