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Safety of bempedoic acid in patients at high cardiovascular risk and with statin intolerance.
Bays, HE, Bloedon, LT, Lin, G, Powell, HA, Louie, MJ, Nicholls, SJ, Lincoff, AM, Nissen, SE
Journal of clinical lipidology. 2024;(1):e59-e69
Abstract
BACKGROUND Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins. OBJECTIVE To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies. METHODS CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years. RESULTS In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups. CONCLUSIONS Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid.
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Toxins in Botanical Drugs and Plant-derived Food and Feed - from Science to Regulation: A Workshop Review.
Schrenk, D, Allemang, A, Fahrer, J, Harms, H, Li, X, Lin, G, Mahony, C, Mulder, P, Peijnenburg, A, Pfuhler, S, et al
Planta medica. 2024;(3):219-242
Abstract
In September 2022, the 3rd International Workshop on pyrrolizidine alkaloids (PAs) and related phytotoxins was held on-line, entitled 'Toxins in botanical drugs and plant-derived food and feed - from science to regulation'. The workshop focused on new findings about the occurrence, exposure, toxicity, and risk assessment of PAs. In addition, new scientific results related to the risk assessment of alkenylbenzenes, a distinct class of herbal constituents, were presented. The presence of PAs and alkenylbenzenes in plant-derived food, feed, and herbal medicines has raised health concerns with respect to their acute and chronic toxicity but mainly related to the genotoxic and carcinogenic properties of several congeners. The compounds are natural constituents of a variety of plant families and species widely used in medicinal, food, and feed products. Their individual occurrence, levels, and toxic properties, together with the broad range of congeners present in nature, represent a striking challenge to modern toxicology. This review tries to provide an overview of the current knowledge on these compounds and indicates needs and perspectives for future research.
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Effects of a two meals-a-day ketogenic diet on newly diagnosed obese patients with type 2 diabetes mellitus: A retrospective observational study.
Li, S, Yuan, S, Lin, G, Zhang, J
Medicine. 2023;(43):e35753
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Abstract
To investigate the effects of a two-meals-a-day energy-restricted ketogenic diet (KD) on newly diagnosed obese patients with type 2 diabetes mellitus. In total, 60 obese patients with newly diagnosed type 2 diabetes mellitus were divided into 2 groups: 1 group followed a 2-meals-a-day KD and the other group followed a conventional diabetic diet. Changes in weight, blood glucose, blood lipids, insulin resistance, and uric acid levels were observed before and after 2 months of adhering to the respective diets under energy restriction. Both groups showed significant reductions in weight, waist circumference, body mass index, total cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, fasting blood glucose, fasting insulin, and glycated hemoglobin (P < .05). The twice-daily KD group showed more significant improvements in these parameters compared to the conventional diabetic diet group. In addition, the 2-meals-a-day KD group showed a slight increase in uric acid levels compared to the conventional diabetic diet control group (P < .05). The 2-meals-a-day KD can significantly improve weight, blood glucose, and lipid control in newly diagnosed obese patients with type 2 diabetes mellitus.
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Transcriptomic profiles reveal the characteristics of oocytes and cumulus cells at GV, MI, and MII in follicles before ovulation.
Hu, Y, Zhang, R, Zhang, S, Ji, Y, Zhou, Q, Leng, L, Meng, F, Gong, F, Lu, G, Lin, G, et al
Journal of ovarian research. 2023;(1):225
Abstract
BACKGROUND The oocyte and its surrounding cumulus cells (CCs) exist as an inseparable entity. The maturation of the oocyte relies on communication between the oocyte and the surrounding CCs. However, oocyte evaluation is primarily based on morphological parameters currently, which offer limited insight into the quality and competence of the oocyte. Here, we conducted transcriptomic profiling of oocytes and their CCs from 47 patients undergoing preimplantation genetic testing for aneuploidy (PGT-A). We aimed to investigate the molecular events occurring between oocytes and CCs at different stages of oocyte maturation (germinal vesicle [GV], metaphase I [MI], and metaphase II [MII]). Our goal is to provide new insights into in vitro oocyte maturation (IVM). RESULTS Our findings indicate that oocyte maturation is a complex and dynamic process and that MI oocytes can be further classified into two distinct subtypes: GV-like-MI oocytes and MII-like-MI oocytes. Human oocytes and cumulus cells at three different stages of maturation were analyzed using RNA-seq, which revealed unique transcriptional machinery, stage-specific genes and pathways, and transcription factor networks that displayed developmental stage-specific expression patterns. We have also identified that both lipid and cholesterol metabolism in cumulus cells is active during the late stage of oocyte maturation. Lipids may serve as a more efficient energy source for oocytes and even embryogenesis. CONCLUSIONS Overall, our study provides a relatively comprehensive overview of the transcriptional characteristics and potential interactions between human oocytes and cumulus cells at various stages of maturation before ovulation. This study may offer novel perspectives on IVM and provide a reliable reference data set for understanding the transcriptional regulation of follicular maturation.
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The Assessment of Dietary Organic Zinc on Zinc Homeostasis, Antioxidant Capacity, Immune Response, Glycolysis and Intestinal Microbiota in White Shrimp (Litopenaeus vannamei Boone, 1931).
Yang, J, Wang, T, Lin, G, Li, M, Zhang, Y, Mai, K
Antioxidants (Basel, Switzerland). 2022;(8)
Abstract
This study aimed to assess dietary organic zinc on zinc homeostasis, antioxidant capacity, immune response, glycolysis and intestinal microbiota in white shrimp (Litopenaeus vannamei Boone, 1931). Six experimental diets were formulated: Control, zinc free; S120, 120 mg·kg-1 zinc from ZnSO4·7H2O added into control diet; O30, O60, O90 and O120, 30, 60, 90 and 120 mg·kg-1 zinc from Zn-proteinate added into control diet, respectively. The results showed that organic zinc significantly promoted zinc content and gene expression of ZnT1, ZIP11 and MT in the hepatopancreas and enhanced antioxidant capacity and immunity (in terms of increased activities of T-SOD, Cu/Zn SOD, PO, LZM, decreased content of MDA, upregulated expressions of GST, G6PDH, ProPO, LZM and Hemo, and increased resistance to Vibrio parahaemolyticus). Organic zinc significantly upregulated GluT1 expression in the intestine, increased glucose content of plasma and GCK, PFK and PDH activities of hepatopancreas, and decreased pyruvate content of hepatopancreas. Organic zinc improved intestinal microbiota communities, increased the abundance of potentially beneficial bacteria and decreased the abundance of potential pathogens. Inorganic zinc (S120) also had positive effects, but organic zinc (as low as O60) could achieve better effects. Overall, organic zinc had a higher bioavailability and was a more beneficial zinc resource than inorganic zinc in shrimp feeds.
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Lipid-Lowering Efficacy of the Capsaicin in Patients With Metabolic Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Jiang, Z, Qu, H, Lin, G, Shi, D, Chen, K, Gao, Z
Frontiers in nutrition. 2022;:812294
Abstract
BACKGROUND Patients with metabolic syndrome (MetS) have increased cardiovascular risk. Capsaicin (CAP) has been shown to reduce lipids, but efficacy for patients with MetS is unknown. METHODS A systematic review was performed according to PRISMA guidelines, to compare the effects of CAP against a placebo. Differences in the weight mean difference (WMD) with 95% confidence intervals (95% CI) were then pooled using a random effects model. RESULTS Nine randomized controlled trials including 461 patients were identified in the overall analysis. CAP significantly decreased total cholesterol (TC) (WMD = -0.48, 95% CI: -0.63 to -0.34, I 2= 0.00%) and low-density lipoprotein cholesterol (LDL-C) (WMD = -0.23, 95% CI: -0.45 to -0.02, I 2 = 68.27%) among patients with MetS. No significant effects of CAP were found on triglycerides (TG) or high-density lipoprotein cholesterol (HDL-C) (WMD = -0.40, 95% CI: -1.50 to 0.71, I 2 = 98.32%; WMD = -0.08, 95% CI: -0.21 to 0.04, I 2 = 86.06%). Subgroup analyses indicated that sex and intervention period were sources of heterogeneity. The results revealed that CAP decreased TG levels in women (WMD = -0.59, 95% CI: -1.07 to -0.10) and intervention period <12 weeks (WMD = -0.65; 95% CI: -1.10 to -0.20). And there was no potential publication bias according to funnel plot, Begg' test and Egger regression test. CONCLUSIONS CAP supplementation is a promising approach to decreasing TC and LCL-C levels in patients with MetS. However, short-term (<12 weeks) use of CAP in women may also reduce TG levels. SYSTEMATIC REVIEW REGISTRATION Identifier: CRD42021228032.
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The effect of periodic ketogenic diet on newly diagnosed overweight or obese patients with type 2 diabetes.
Li, S, Lin, G, Chen, J, Chen, Z, Xu, F, Zhu, F, Zhang, J, Yuan, S
BMC endocrine disorders. 2022;22(1):34
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Currently, the ketogenic diet is gaining popularity in managing Type 2 diabetes (T2D). Ketogenic diets replace carbohydrates with fat and include limited carbohydrates and adequate protein. This randomised controlled trial evaluated the effects of the 12-week ketogenic diet on sixty overweight or obese T2D patients. Both the ketogenic and control diabetes diet groups achieved significant reductions in weight, body mass index, waist circumference, triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, fasting blood glucose, fasting insulin, and HbA1c. However, the ketogenic group showed significantly greater reductions in body mass, blood lipids, and blood glucose than the control group. In the ketogenic diet group, serum uric acid levels were higher than those in the control diet group. It was found that the control diet group adhered to the diet for a longer period than the ketogenic diet group, whose willingness to adhere to the diet long-term was weaker. More robust long-term studies are needed to evaluate the long-term effects of a ketogenic diet. In this study, more patients who followed the ketogenic diet experienced hypoglycaemic events during the first four weeks. Healthcare providers should exercise caution when recommending a short term therapeutic ketogenic diet.
Abstract
BACKGROUND The ketogenic diet (KD) is characterized by fat as a substitute of carbohydrates for the primary energy source. There is a large number of overweight or obese people with type 2 diabetes mellitus (T2DM), while this study aims to observe periodic ketogenic diet for effect on overweight or obese patients newly diagnosed as T2DM. METHODS A total of 60 overweight or obese patients newly diagnosed as T2DM were randomized into two groups: KD group, which was given ketogenic diet, and control group, which was given routine diet for diabetes, 30 cases in each group. Both dietary patterns lasted 12 weeks, and during the period, the blood glucose, blood lipid, body weight, insulin, and uric acid before and after intervention, as well as the significance for relevant changes, were observed. RESULTS For both groups, the weight, BMI(body mass index), Waist, TG (triglyceride), TC(cholesterol), LDL (low-density lipoprotein cholesterol), HDL (high-density lipoprotein cholesterol), FBG (fasting glucose), FINS (fasting insulin), HbA1c (glycosylated hemoglobin) were decreased after intervention (P < 0.05), while the decrease rates in the KD group was more significant than the control group. However, UA(serum uric acid) in the KD group showed an upward trend, while in the control group was not changed significantly (P > 0.05).The willingness to adhere to the ketogenic diet over the long term was weaker than to the routine diet for diabetes. CONCLUSION Among the overweight or obese patients newly diagnosed as type 2 diabetes mellitus, periodic ketogenic diet can not only control the body weight, but also control blood glucose and lipid, but long-term persistence is difficult.
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Systemic lupus erythematosus simultaneously presenting with visceral muscle dysmotility syndrome and mechanical intestinal obstruction clinically relieved by surgery: a case report and literature review.
Wen, J, Chen, W, Gao, L, Qiu, X, Lin, G
BMC gastroenterology. 2022;(1):32
Abstract
BACKGROUND Intestinal pseudo-obstruction (IPO) accompanied by hepatobiliary dilatation and ureterohydronephrosis is extremely rare in systemic lupus erythematosus (SLE). This triad is also called visceral muscle dysmotility syndrome (VMDS). Only 9 cases have been reported in the literature. Here, we report a rare case of VMDS with mechanical intestinal obstruction that was clinically relieved by surgery. CASE PRESENTATION This report refers to a 31-year-old woman with SLE and gastrointestinal symptoms presented as abdominal pain, nausea and stoppage of the passage of flatus or stool without obvious reasons. The patient suffered from severe abdominal distension because of massive flatulence. Contrast-enhanced computed tomography (CT) of the abdomen performed in our hospital showed localized stenosis of the bowel, ureterohydronephrosis, and biliary tract dilatation. Endoscopy showed a stenotic segment located in the sigmoid colon. The colon biopsy samples suggested that the stenosis was caused by inflammatory tissues. Biochemical investigations showed hypoalbuminemia, electrolyte disturbance and decreased C3. Antinuclear antibody was positive. After careful assessment, transverse colostomy was performed for this patient. Gastrointestinal symptoms were clinically relieved after the surgery. CONCLUSION To the best of our knowledge, no VMDS patients have presented with mechanical ileus before. This case is the first documented occurrence of SLE with VMDS and mechanical intestinal obstruction symptoms relieved by surgery. Due to the low incidence of this condition, no standard treatment regimen has been established. However, surgical treatment offers significant benefit in specific situations.
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Tu-San-Qi (Gynura japonica): the culprit behind pyrrolizidine alkaloid-induced liver injury in China.
Zhu, L, Zhang, CY, Li, DP, Chen, HB, Ma, J, Gao, H, Ye, Y, Wang, JY, Fu, PP, Lin, G
Acta pharmacologica Sinica. 2021;(8):1212-1222
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Abstract
Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatomegaly, hyperbilirubinemia, and ascites. In China, G. japonica has been used as one of the plant species for Tu-San-Qi and is often misused with non-PA-producing Tu-San-Qi (Sedum aizoon) or even San-Qi (Panax notoginseng) for self-medication. It has been reported that over 50% of HSOS cases are caused by the intake of PA-producing G. japonica. In this review, we provide comprehensive information to distinguish these Tu-San-Qi-related herbal plant species in terms of plant/medicinal part morphologies, medicinal indications, and chemical profiles. Approximately 2156 Tu-San-Qi-associated HSOS cases reported in China from 1980 to 2019 are systematically reviewed in terms of their clinical manifestation, diagnostic workups, therapeutic interventions, and outcomes. In addition, based on the application of our developed mechanism-based biomarker of PA exposure, our clinical findings on the definitive diagnosis of 58 PA-producing Tu-San-Qi-induced HSOS patients are also elaborated. Therefore, this review article provides the first comprehensive report on 2214 PA-producing Tu-San-Qi (G. japonica)-induced HSOS cases in China, and the information presented will improve public awareness of the significant incidence of PA-producing Tu-San-Qi (G. japonica)-induced HSOS and facilitate future prevention and better clinical management of this severe HILI.
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Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial.
Orkin, C, Squires, KE, Molina, JM, Sax, PE, Sussmann, O, Lin, G, Kumar, S, Hanna, GJ, Hwang, C, Martin, E, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;(1):33-42
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BACKGROUND Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. METHODS DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96. RESULTS Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, -2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar. CLINICAL TRIALS REGISTRATION NCT02403674.