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Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.
Huang, YY, Lin, CW, Cheng, NC, Cazzell, SM, Chen, HH, Huang, KF, Tung, KY, Huang, HL, Lin, PY, Perng, CK, et al
JAMA network open. 2021;(9):e2122607
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Abstract
IMPORTANCE Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. OBJECTIVE To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. DESIGN, SETTING, AND PARTICIPANTS This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. INTERVENTIONS Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. MAIN OUTCOMES AND MEASURES The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. RESULTS In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. CONCLUSIONS AND RELEVANCE In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01898923.
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Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.
Wang, S, Ma, P, Zhang, S, Song, S, Wang, Z, Ma, Y, Xu, J, Wu, F, Duan, L, Yin, Z, et al
Diabetologia. 2020;63(10):2102-2111
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Plain language summary
Hyperglycaemia was a risk factor for mortality from severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and is an independent risk factor for lower respiratory tract infection and poor prognosis. The aim of this retrospective study of 605 patients without previously diagnosed diabetes was to examine the association between fasting blood glucose (FBG) on admission and the 28-day in hospital mortality of COVID-19 patients. Patients with a FBG level of 7.0mmol/l or over had more than double the risk of dying than those with a level of 6.0mmol/l or less. Other risk factors for mortality included age, being male, and severity of pneumonia at admission. Compared with patients whose FBG was 6.0mmol/l or lower at admission, patients with FBG of 7.0 mmol/l and above had a 3.99 times higher risk of in-hospital complications, whilst those with FBG of 6.1–6.9 mmol/l had a 2.61 times higher risk of complications. The authors conclude that glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes.
Abstract
AIMS/HYPOTHESIS Hyperglycaemia is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, acute myocardial infarction, trauma and surgery, among other conditions. In this study, we examined the relationship between fasting blood glucose (FBG) and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed as having diabetes. METHODS We conducted a retrospective study involving all consecutive COVID-19 patients with a definitive 28-day outcome and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. CRB-65 is an effective measure for assessing the severity of pneumonia and is based on four indicators, i.e. confusion, respiratory rate (>30/min), systolic blood pressure (≤90 mmHg) or diastolic blood pressure (≤60 mmHg), and age (≥65 years). RESULTS Six hundred and five COVID-19 patients were enrolled, including 114 who died in hospital. Multivariable Cox regression analysis showed that age (HR 1.02 [95% CI 1.00, 1.04]), male sex (HR 1.75 [95% CI 1.17, 2.60]), CRB-65 score 1-2 (HR 2.68 [95% CI 1.56, 4.59]), CRB-65 score 3-4 (HR 5.25 [95% CI 2.05, 13.43]) and FBG ≥7.0 mmol/l (HR 2.30 [95% CI 1.49, 3.55]) were independent predictors for 28-day mortality. The OR for 28-day in-hospital complications in those with FBG ≥7.0 mmol/l and 6.1-6.9 mmol/l vs <6.1 mmol/l was 3.99 (95% CI 2.71, 5.88) or 2.61 (95% CI 1.64, 4.41), respectively. CONCLUSIONS/INTERPRETATION FBG ≥7.0 mmol/l at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. Graphical abstract.
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Effect of Omega-3 Supplementation in Patients With Smell Dysfunction Following Endoscopic Sellar and Parasellar Tumor Resection: A Multicenter Prospective Randomized Controlled Trial.
Yan, CH, Rathor, A, Krook, K, Ma, Y, Rotella, MR, Dodd, RL, Hwang, PH, Nayak, JV, Oyesiku, NM, DelGaudio, JM, et al
Neurosurgery. 2020;(2):E91-E98
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Abstract
BACKGROUND Endoscopic endonasal approaches pose the potential risk of olfactory loss. Loss of olfaction and potentially taste can be permanent and greatly affect patients' quality of life. Treatments for olfactory loss have had limited success. Omega-3 supplementation may be a therapeutic option with its effect on wound healing and nerve regeneration. OBJECTIVE To evaluate the impact on olfaction in patients treated with omega-3 supplementation following endoscopic skull base tumor resection. METHODS In this multi-institutional, prospective, randomized controlled trial, 110 patients with sellar or parasellar tumors undergoing endoscopic resection were randomized to nasal saline irrigations or nasal saline irrigations plus omega-3 supplementation. The University of Pennsylvania Smell Identification Test (UPSIT) was administered preoperatively and at 6 wk, 3 mo, and 6 mo postoperatively. RESULTS Eighty-seven patients completed all 6 mo of follow-up (41 control arm, 46 omega-3 arm). At 6 wk postoperatively, 25% of patients in both groups experienced a clinically significant loss in olfaction. At 3 and 6 mo, patients receiving omega-3 demonstrated significantly less persistent olfactory loss compared to patients without supplementation (P = .02 and P = .01, respectively). After controlling for multiple confounding variables, omega-3 supplementation was found to be protective against olfactory loss (odds ratio [OR] 0.05, 95% CI 0.003-0.81, P = .03). Tumor functionality was a significant independent predictor for olfactory loss (OR 32.7, 95% CI 1.15-929.5, P = .04). CONCLUSION Omega-3 supplementation appears to be protective for the olfactory system during the healing period in patients who undergo endoscopic resection of sellar and parasellar masses.
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Effect of B vitamins supplementation on cardio-metabolic factors in patients with stable coronary artery disease: A randomized double-blind trial.
Liu, M, Wang, Z, Liu, S, Liu, Y, Ma, Y, Liu, Y, Xue, M, Li, Q, Zhang, X, Zhang, S, et al
Asia Pacific journal of clinical nutrition. 2020;(2):245-252
Abstract
BACKGROUND AND OBJECTIVES This study aimed to evaluate whether B vitamins supplementation would improve dyslipidemia, alleviate inflammatory state of patients with stable coronary artery disease (SCAD). METHODS AND STUDY DESIGN We conducted a randomized, double-blind, 12-week, placebo-controlled trial involving adults with SCAD, and who were randomly divided into B vitamins group (folic acid and VB-6) and control group (placebo tablet). Blood tests had also been performed at baseline and endpoint. RESULTS After 12 weeks of intervention, B vitamins supplementation significantly improved the concentration of serum TG, TC and HDL-C (p<0.05). Changes of serum homocysteine in B vitamins treatment were significantly different compared to placebo by the multivariate-adjusted analysis (3.02±2.35 vs 1.55±1.58 p<0.001). Meanwhile, the levels of IL-1β and IL-10, significant difference were observed between two groups after adjustment for confounding factors. CONCLUSIONS Supplementation with B vitamins significantly improves lipid metabolism, alleviate inflammation and serum homocysteine concentration in patients with SCAD.
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The effect of BCM guided dry weight assessment on short-term survival in Chinese hemodialysis patients : Primary results of a randomized trial - BOdy COmposition MOnitor (BOCOMO) study.
Liu, L, Sun, Y, Chen, Y, Xu, J, Yuan, P, Shen, Y, Lin, S, Sun, W, Ma, Y, Ren, J, et al
BMC nephrology. 2020;(1):135
Abstract
BACKGROUND Lack of accurate and effective assessment tools of fluid status is one of the major challenges to reach proper dry weight (DW) in chronic hemodialysis (HD) population. The aim of this randomized study was to evaluate the effect of bioimpedance guided DW assessment on long-term outcomes in Chinese HD patients. Eligible patients were randomly assigned (1:1) to two groups in each center, the control group and body composition monitor (BCM) group. In the BCM group, DW has been evaluated by bioimpedance technic every 2 months during follow-up. The primary composite endpoint consisted of death, acute myocardial infarction, cerebral infarction, cerebral hemorrhage, and peripheral vascular disease. METHODS A total of 445 patients were recruited from 11 hemodialysis centers from Beijing, Tianjin and Shijiazhuang cities from Jan 1, 2013 to Dec 31, 2014. They were randomized into either BCM group or control group. All patients have been followed up for 1 year or until Dec 31, 2014 or censoring. RESULTS At baseline, there were no significant differences between two groups in terms of demographic parameters, dialysis vintage, percentage of vascular access, and comorbid conditions. At the end of the study, 18 (4.04%) patients had died (11 in control group and 7 in BCM group). Kaplan-Meier survival analysis showed no significant difference in survival rates between two groups (log-rank test P = 0.07). However, there was an increasing trend of survival rates in BCM group compared to the control group. In the multivariable Cox analysis, there was a nonsignificant trend toward less primary composite end points in the BCM group in the adjusted analysis, the hazard ratio was impressive (0.487, 95% CI 0.217-1.091, P = 0.08). CONCLUSION Bioimpedance technic has been applied to assess fluid status for decades and has been proved to be a promising tool for clinical practice. Although short-term outcomes were not improved in the randomized, controlled trial, the ascending trend in survival has been observed. Further studies are needed to investigate the survival benefit of bioimpedance method in DW assessment in a larger sample with longer follow-up period. TRIAL REGISTRATION ClinicalTrials.org, NCT01509937. Registered 13 January 2012.
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Serum milk fat globule-EGF factor 8 (MFG-E8) as a diagnostic and prognostic biomarker in patients with hepatocellular carcinoma.
Shimagaki, T, Yoshio, S, Kawai, H, Sakamoto, Y, Doi, H, Matsuda, M, Mori, T, Osawa, Y, Fukai, M, Yoshida, T, et al
Scientific reports. 2019;(1):15788
Abstract
Current serum hepatocellular carcinoma (HCC) biomarkers are insufficient for early diagnosis. We aimed to clarify whether serum MFG-E8 can serve as a diagnostic or prognostic biomarker of HCC. Serum MFG-E8 levels of 282 HCC patients, who underwent primary hepatectomy, were examined by ELISA. We also quantified serum MFG-E8 levels in patients with chronic hepatitis (CH), liver cirrhosis (LC), as well as in healthy volunteers (HVs). Serum MFG-E8 levels were significantly lower in HCC patients than in HVs regardless of the etiology of liver disease (3.6 ± 0.1 vs 5.8 ± 0.2 ng/mL, p < 0.0001), and recovered after treatment of HCC. Serum MFG-E8 levels in CH and LC patients were comparable to those in HVs. Serum MFG-E8 could detect HCCs, even α-fetoprotein (AFP)-negative or des-γ-carboxy prothrombin (DCP)-negative HCCs, in CH and LC patients. Our new HCC prediction model using MFG-E8 and DCP (Logit(p) = 2.619 - 0.809 × serum MFG-E8 + 0.0226 × serum DCP) distinguished HCC patients from CH and LC patients with an area under the curve of 0.923, a sensitivity of 81.1%, and a specificity of 89.8%. Futhermore, low preoperative serum MFG-E8 was an independent predictor of poor overall survival. Thus, serum MFG-E8 could serve as a feasible diagnostic and prognostic biomarker for HCC.
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Optimizing early enteral nutrition in severe stroke (OPENS): protocol for a multicentre randomized controlled trial.
Yuan, F, Yang, F, Zhang, W, Jia, Y, Ma, Y, Qu, Y, Wang, X, Huo, K, Wang, C, Yuan, X, et al
BMC neurology. 2019;(1):24
Abstract
BACKGROUND Malnutrition is one of the crucial factors associated with poor prognosis in critical ill patients, yet a significant evidence gap surrounds the management of initial enteral feeding in severe stroke. The Optimizing Early Enteral Nutrition in Severe Stroke (OPENS) trial will compare a strategy of modified full enteral nutrition (EN) (standard full EN in conjunction with prokinetic drug) and a strategy of permissive underfeeding (40 to 60% of estimated caloric requirements) with standard full EN (advancement to target nutrition goals) in patients with severe stroke. METHODS The OPENS trial is a multicenter randomized controlled study. A total of 600 adult patients with severe stroke will be enrolled in 12 study sites in China, and randomized to standard full EN, modified full EN, or permissive underfeeding. The primary outcome measurement is the proportion of participants with a poor outcome (modified Rankin Scale ≥3) at day 90 of enrollment. Secondary outcomes include incidence rates of complications during hospitalization, disability at hospital discharge, and the ability of activities of daily living at day 90 of enrollment. The relationship between intervention and the primary outcome will be analyzed using multivariate logistic regression adjusted for study site, demographics, and baseline characteristics. DISCUSSION The OPENS trial will explore the optimum initial feeding strategy for acute severe stroke. This trial is, therefore, an important step in bridging the evidence gap surrounding the enteral feeding for patients with severe stroke during the first week of hospitalization. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02982668 ; First Posted: December 5, 2016.
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Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 studies.
Stroes, E, Robinson, JG, Raal, FJ, Dufour, R, Sullivan, D, Kassahun, H, Ma, Y, Wasserman, SM, Koren, MJ
Clinical cardiology. 2018;(10):1328-1335
Abstract
BACKGROUND Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. HYPOTHESIS LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. METHODS A total of 3146 patients received ≥1 dose of evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. RESULTS In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control. CONCLUSIONS Consistent reductions in LDL-C were observed in the evolocumab group regardless of demographic and disease characteristics.
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Early sorafenib-related adverse events predict therapy response of TACE plus sorafenib: A multicenter clinical study of 606 HCC patients.
Zhao, Y, Li, H, Bai, W, Liu, J, Lv, W, Sahu, S, Guan, S, Qin, X, Wang, W, Ren, W, et al
International journal of cancer. 2016;(4):928-37
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Abstract
The purpose of our study was to test the hypothesis that sorafenib-related dermatologic adverse events (AEs) as an early biomarker can predict the long-term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (TACE-S). The intermediate-stage hepatocellular carcinoma patients who received either TACE-S or TACE-alone treatment were consecutively included into analysis. In the TACE-S group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with < grade 2 were defined as nonresponders. In the TACE-S group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; p = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval-CI: 1.3-2.7; p = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0-30.8) among responders treated with TACE-S vs.18.3 months (95% CI: 14.5-22.1) among those who received TACE-alone (p = 0.046). The median time to progression was 13.1 months (95% CI: 4.4-21.8) in the TACE-S group, a duration that was significantly longer than that in the TACE-alone group [5 months (95% CI: 6.4-13.3), p = 0.014]. This study demonstrated that sorafenib-related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for TACE-S therapy. Sorafenib-related dermatologic AEs, clinical biomarkers, can predict the efficacy of TACE-S in future randomized controlled trials.
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Long-term prevalence and predictors of urinary incontinence among women in the Diabetes Prevention Program Outcomes Study.
Phelan, S, Kanaya, AM, Ma, Y, Vittinghoff, E, Barrett-Connor, E, Wing, R, Kusek, JW, Orchard, TJ, Crandall, JP, Montez, MG, et al
International journal of urology : official journal of the Japanese Urological Association. 2015;(2):206-12
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Abstract
OBJECTIVES To examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study, a follow-up study of the Diabetes Prevention Program randomized clinical trial of overweight adults with impaired glucose tolerance. METHODS This analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been randomly assigned during the Diabetes Prevention Program to intensive lifestyle intervention (n = 582), metformin (n = 589) or placebo (n = 607). The study participants completed semi-annual assessments after the final Diabetes Prevention Program visit and for 6 years until October 2008. RESULTS At the study entry, the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups (44.2% vs 51.8%, 48.0% urinary incontinence/week, P = 0.04); during the 6-year follow-up period, these lower rates in intensive lifestyle intervention were maintained (46.7%, 53.1%, 49.9% urinary incontinence/week; P = 0.03). Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program, the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study. Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index (odds ratio 0.988, 95% confidence interval 0.982-0.994) and greater physical activity (odds ratio 0.999, 95% confidence interval 0.998-1.000) at the Diabetes Prevention Program Outcomes Study entry, and greater reductions in body mass index (odds ratio 0.75, 95% confidence interval 0.60-0.94) and waist circumference (odds ratio 0.998, 95% confidence interval 0.996-1.0) during the Diabetes Prevention Program Outcomes Study. Diabetes was not significantly related to urinary incontinence. CONCLUSIONS Intensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence, and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance.