Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4⁺ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection.METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4⁺ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment.RESULTS. Frequencies of Mtb-specific IFN-γ⁺CD4⁺ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38⁺IFN-γ⁺, HLA-DR⁺IFN-γ⁺, and Ki-67⁺IFN-γ⁺, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4⁺ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure.TRIAL REGISTRATION. Registration is not required for observational studies.FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.     

Trade-offs between acquired and innate immune defenses in humans

Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology.     

HER2-positive advanced breast cancer treatment in 2020

HER2-positive breast cancer is an aggressive subtype identified in the 1980s. The development of therapies targeting the HER2 has improved outcomes. The current standard of care, established in 2012 is dual blockade with trastuzumab + pertuzumab as first-line followed by TDM-1 as second-line. Several suboptimal choices are available in third-line or more. In 2019 the presentation of several trials evaluating new drugs and regimens in third-line has re-opened questions about sequencing, treatment of triple positive disease and treatment choice after exposure to TDM-1. These include tucatinib, neratinib and trastuzumab-deruxtecan. Other agents – including other antibody drug conjugates and bispecific antibodies as well as combinations - will lead to further changes in coming years. Additionally, should the numerous putative biomarkers thus identified ever come into use at the clinic, choice of treatment and response evaluation may be substantially changed.     

美托洛尔用于老年COPD合并冠心病史治疗的临床疗效观察

目的:探讨美托洛尔(β1受体阻滞剂)用于老年COPD合并冠心病史治疗的临床疗效。方法:选取2018年6月—2019年6月在我院接受治疗的60岁以上(包括60岁)COPD合并冠心病史老年患者,分为对照组与观察组。对照组给予接受布地奈德福莫特罗粉吸入剂治疗,观察组在使用布地奈德福莫特罗粉吸入剂治疗的基础上口服琥珀酸美托洛尔缓释片治疗,观察对比两组治疗效果。结果:观察组临床治疗效果优于对照组,观察组住院时长以及并发症的发生率低于对照组(P<0.05),差异具有统计学意义。结论:老年COPD合并冠心病史接受美托洛尔治疗,可有效缩短住院时长、用药效果明显、有效提升用药安全性,值得临床推广。     

Association of four CpG-SNPs in the vascular-related genes with coronary heart disease

Vascular-related gene polymorphism can affect the susceptibility of coronary heart disease. In current study, we aimed to evaluate the contribution of four vascular-related gene CpG-SNPs to coronary heart disease (CHD). A total of 784 angiography-proven CHD patients and 746 non-CHD controls were included in the current association study. The four CpG-SNPs (including VEGFA rs1005230, ACE rs4316, CST3 rs3827143 and AGTR1 rs275653) were genotyped using the Sequenom MassARRAY platform. All genotype distribution of four SNPs met HWE. Among the four CpG-SNPs, none was found to be associated with CHD on both genotype and allele levels. Further subgroup tests by age or gender were unable to observe any significant associations of them with CHD. Our case-control study showed that none of four CpG-SNPs in the vascular-related genes was associated with the risk of CHD in Han Chinese, although we could not exclude other genetic variants of these vascular-related genes with contribution to CHD.     

The effects of carnitine supplementation on clinical characteristics of patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

ObjectiveThe beneficial effects of carnitine supplementation on nonalcoholic fatty liver disease are unclear. We conducted a systematic review and meta-analysis to evaluate the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance in patients with nonalcoholic fatty liver disease.MethodsA comprehensive search of PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar databases were performed. Only randomized placebo-controlled human studies that examined the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance up to September 2019 were included. Fixed effects or random-effects models were applied to compute the pooled effect size. Heterogeneity assessments were performed using Cochran’s Q test and I-squared statistics. The quality of the studies was assessed using the Jaded scale.ResultsA total of 5 articles were selected, including 334 individuals (167 in control and 167 in intervention groups). The results demonstrated that carnitine supplementation significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) (WMD: −0.91; 95 % CI: −1.11, −0.72; p < 0.001, I² = 0.0 %) and the levels of aspartate aminotransferase (AST) (WMD: −16.62; 95 % CI: −28.11, −5.14; IU/l; p = 0.005, I² = 93.5 %), alanine aminotransferase (ALT) (WMD: -33.39; 95 % CI: −45.13, −21.66; IU/l; p < 0.001, I² = 93.4 %), and triglycerides (TG) (WMD: −22.13; 95 % CI: −38.91, −5.34; mg/dl; p = 0.01; I² = 0.0 %). However, the results of the pooled effect size did not show any significant effect of carnitine supplementation on body mass index (BMI) (WMD: 0.07; 95 % CI: −0.15, 0.29; p = 0.55; I² = 0.0 %), body weight (WMD: −0.28; 95 % CI: −2.23, 1.68; p = 0.78; I² = 45.7 %), the levels of gamma-glutamyl transferase (γGT) (WMD: −11.31; 95 % CI: −24.35, 1.73; IU/l; p = 0.09, I² = 61.1 %), cholesterol (WMD: −13.58; 95 % CI: −46.77, 19.60; mg/dl; p = 0.42; I² = 94.9 %), high-density lipoprotein-cholesterol (HDL-C) (WMD: 1.36; 95 % CI: −0.96, 3.68; mg/dl; p = 0.25; I² = 64.7 %), and low density lipoprotein-cholesterol (LDL-C) (WMD: −14.85; 95 % CI: −45.43, 15.73; mg/dl; p = 0.34; I² = 96.4 %).ConclusionsThis analysis shows that carnitine supplementation for patients with nonalcoholic fatty liver disease demonstrates a reduction in AST, ALT, TG levels and HOMA-IR. However, no significant effect of carnitine supplementation was observed on BMI, body weight, the levels of γGT, TC, HDL-cholesterol and LDL-cholesterol.     

探讨替米沙坦对冠心病合并糖尿病肾病患者疗效的影响

目的:探究替米沙坦对冠心病合并糖尿病肾病患者疗效的影响情况。方法:56例探究目标对象均为某院接收的冠心病合并糖尿病肾病患者,挑选时间2018年6月~2019年6月。将"计算机表法"作为分组的参考,分配为参照组(n=28例)执行依那普利治疗,探究组(n=28例)执行替米沙坦治疗。结果:探究组的LVEF、LVEDd、肌酐、24h尿蛋白4项指标与参照组相比,差异有统计学意义(P<0.05);收缩压、舒张压、空腹血糖、餐后2h血糖4项指标与参照组相比,差异没有统计学意义(P>0.05)。结论:冠心病合并糖尿病肾病患者选择替米沙坦治疗后,心室功能的重构以及肾脏预后结局均得到改善,且临床效果比依那普利好,值得借鉴。