Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

1. Download : Download high-res image (451KB)
2. Download : Download full-size image

     

Associations between serum amino acids and incident type 2 diabetes in Chinese rural adults

Background and aimsSome amino acids (AAs) may be associated with type 2 diabetes (T2DM). This study aimed to determine the associations of individual AAs with the development of T2DM in rural Chinese adults.Methods and resultsA cohort study of 1199 individuals aged 18 years or older was conducted from 2006 to 2008 in a rural community of Deqing, China, a repeated survey was done in 2015 and data linkage with the electronic health records system was performed each year for identifying new T2DM cases. A high-performance liquid chromatography approach was used to measure the baseline serum concentrations of 15 AAs. Cox proportional hazards models were used to examine the associations between AAs and the risk of incident T2DM. A total of 98 new T2DM cases were identified during the follow-up of 12 years on average. Among 15 AAs, proline was associated with an increased risk of incident T2DM after adjusted for age, sex, body mass index, fasting plasma glucose, family history of T2DM, smoking status, alcohol use, and history of hypertension, the adjusted hazard ratio for 1-standard deviation increment was 1.20 (95% confidence interval: 1.00, 1.43). The association tended to be more marked in subjects younger than 60 years and overweight/obese subjects. Among participants without hypertension, proline and phenylalanine were associated with an increased risk of incident T2DM, while aspartic acid was associated with a decreased risk.ConclusionSerum proline was associated with the risk of incident T2DM in rural Chinese adults and might be a potential predictor.     

Uveitis in Patients Treated with CTLA-4 and PD-1 Checkpoint Blockade Inhibition

ABSTRACT

Purpose: To investigate the link between treatment with CTLA-4 and PD-1 checkpoint blockade inhibitors and the development of noninfectious uveitis.

Methods: A survey was distributed to uveitis specialists to identify patients who developed uveitis while receiving either PD-1 inhibitors pembrolizumab and nivolumab; PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; or the CTLA-4 inhibitor ipilimumab.

Results: Fifteen patients from seven institutions were identified. The most common cancer diagnosis (13/15) was malignant melanoma. Fourteen patients had a new uveitis diagnosis following checkpoint blockade administration (six anterior uveitis, six panuveitis, one posterior uveitis, one anterior/intermediate combined); one patient developed optic neuritis. Uveitis was diagnosed within 6 months after drug initiation for 11/12 patients (median 63 days). Corticosteroid treatment was effective for most patients, although two patients had permanent loss of vision.

Conclusions: Patients on checkpoint inhibitor therapy should be educated to seek care if they develop ocular symptoms, and prompt referral to specialists should be incorporated into oncology protocols.     

Is interleukin-2 an optimal marker for diagnosing tuberculosis infection? A systematic review and meta-analysis

Abstract

Background

Latent tuberculosis infection (LTBI) is a huge reservoir for the deadlier TB disease. Accurate identification of LTBI is a key strategy to eliminate TB. Therefore, a systematic review and meta-analysis approach was used to assess diagnostic potential of IL-2 for LTBI.     

Pharmacokinetics,Pharmacodynamics, and Exposure‐Response of Lanadelumab for Hereditary Angioedema

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (C_min,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Hereditary angioedema (HAE) is a long‐term, debilitating, and potentially life‐threatening disease caused by C1‐inhibitor deficiency. Lanadelumab is a fully human monoclonal antibody inhibitor of plasma kallikrein that is effective in preventing attacks in patients with HAE.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What are the pharmacokinetic and pharmacodynamic characteristics of lanadelumab, and how are they related to the observed efficacy of lanadelumab in preventing HAE attacks?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Lanadelumab clearance and volume of distribution are dependent on body weight; however, significant attack rate reduction is still observed in patients with high body weight, and dose adjustment is not necessary. The findings of this study provide a greater understanding of the factors driving the efficacy and safety of lanadelumab to ensure optimal use.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Selective binding of lanadelumab to plasma kallikrein provides a novel approach for long‐term prophylaxis against HAE attacks.

Hereditary angioedema (HAE) is a rare, debilitating, and potentially life‐threatening disease with an estimated prevalence of 1 in 50,000. ¹ It manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Swelling may last several days, and most patients have multiple attacks per year. ² Symptoms usually begin during childhood, sometimes as young as age 2 years, and persist throughout life. ² HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1‐INH), resulting in deficiency of C1‐INH protein or function. ³ C1‐INH is involved in regulating the contact, complement, and coagulation systems. ³ In the contact system, C1‐INH is the natural inhibitor of plasma kallikrein. Dysregulated contact system activation and subsequent uncontrolled plasma kallikrein activity lead to production of cleaved high molecular weight kininogen (cHMWK) and the edema‐inducing peptide bradykinin, which initiates signaling pathways leading to HAE attacks. Management of patients with HAE involves on‐demand medications to treat attacks when they occur, and long‐term or short‐term prophylaxis to prevent attacks. ¹ , ² Lanadelumab is a fully human immunoglobulin G1 monoclonal antibody that binds specifically to active plasma kallikrein. ⁴ It is approved in several countries for the prevention of HAE attacks in patients ≥ 12 years of age. In clinical trials, treatment with lanadelumab significantly reduced attack rates in patients with HAE, and this was associated with a reduction in cHMWK levels. ⁵ , ⁶ The pharmacokinetics (PK), pharmacodynamics (PD), exposure‐response relationships, and potential interactions of lanadelumab with rescue medications (for treatment of attacks that occur during long‐term prophylaxis), and with medications commonly used concomitantly in patients with HAE, were characterized using data from clinical studies to support the dosing rationale for long‐term prophylaxis with lanadelumab in patients with HAE.     

Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment

Stem cell transplantation has brought new hope for the treatment of neurological diseases.The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells.Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors,the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located.Accordingly,the optimal microenvironment for inducing stem cell differentiation is a hot topic.EGb761 is extracted from the leaves of the Ginkgo biloba tree.It is used worldwide and is becoming one of the focuses of stem cell research.Studies have shown that EGb761 can antagonize oxygen free radicals,stabilize cell membranes,promote neurogenesis and synaptogenesis,increase the level of brain-derived neurotrophic factors,and replicate the environment required during the differentiation of stem cells into nerve cells.This offers the possibility of using EGb761 to induce the differentiation of stem cells,facilitating stem cell transplantation.To provide a comprehensive reference for the future application of EGb761 in stem cell therapy,we reviewed studies investigating the influence of EGb761 on stem cells.These started with the composition and neuropharmacology of EGb761,and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.