Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Thromboelastography (TEG)-based algorithm reduces blood product utilization in patients undergoing VAD implant.

OBJECTIVES: Multiple blood products are often required during and after ventricular assist device (VAD) implants. Generally, transfusion therapy is empirically guided by conventional laboratory tests. In this study, we aimed to compare a thromboelastography (TEG)-based algorithm with a laboratory coagulation test-based algorithm with respect to blood product utilization in patients undergoing VAD implant. METHODS: From June 2010 to May 2012, a total of 39 consecutive patients underwent VAD implantation. Patients undergoing VAD implant were retrospectively divided into two groups according to transfusion strategy. In the control group (n=20), the need for blood transfusion was based on clinician's discretion according to standard coagulation test results. In the TEG group (n=19), a strict protocol based on TEG parameters was followed for the usage of all perioperative blood products. Coagulation factors, TEG parameters, and blood transfusions were documented and compared between these two groups. RESULTS: There were no differences in demographic variables with the exception of a decreased CPB time in the TEG group (p=0.019). Prothrombin time (PT) (p<0.001) and international normalized ratio (INR) (p<0.001) in the postprotamine interval were significantly higher in the TEG group than in the control group. No significant difference was detected in any coagulation variable in the postoperative (ICU) period between the two groups. Platelet counts decreased in a linear fashion from baseline to the postoperative period in the two groups (p<0.001). Patients in the TEG group received significantly less fresh-frozen plasma in both the intraoperative (p=0.005) and postoperative (p=0.014) periods. Patients in the TEG group also received significantly less platelets both in the postoperative (p=0.03) period and in total amount (p=0.033). There was no difference in consumption of packed red blood cell units between the two groups. CONCLUSIONS: Our results show that the strict use of a TEG-guided algorithm significantly reduces the consumption of blood products in patients undergoing VAD implant

Topotecan plus carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate whether the addition of topotecan can improve the efficacy of carboplatin and paclitaxel in first-line treatment of advanced epithelial ovarian cancer. METHODS: Meta-analysis was performed using a random effects model. RESULTS: Four randomized controlled trials with a total of 3632 patients were identified and included in the meta-analysis. No significant differences were observed in terms of progression-free survival (P=0.400), overall survival (P=0.502) and overall response rate (P=0.953) between patients treated with topotecan plus carboplatin and paclitaxel versus carboplatin and paclitaxel. However, there were significantly higher rates of grade 3-4 leucopenia (P=0.024), neutropenia (P<0.001), anaemia (P<0.001), and thrombopenia (P<0.001) in the topotecan plus carboplatin and paclitaxel group. No significant differences were observed in grade 3-4 nausea (P=0.352) and vomiting (P=0.092) between these two groups. CONCLUSION: Topotecan plus carboplatin and paclitaxel did not improve survival outcomes and caused more haematological toxicity for advanced ovarian cancer.

The impact of pulmonary hypertension on outcomes of patients with low left ventricular ejection fraction: a propensity analysis.

BACKGROUND AND AIM OF THE STUDY: Pulmonary hypertension (PH) is commonly described as a risk factor in cardiac surgery; however, the effect of a low left ventricular ejection fraction (LVEF) on PH has not been assessed. Hence, the study aim was to determine whether PH increases operative mortality and survival outcome in patients with a low LVEF. METHODS: Between January 2001 and September 2009, a total of 845 consecutive patients with LVEF < 40% was enrolled into the study. Among these patients, 444 had a pulmonary pressure < 40 mmHg (NPH group), while in 401 patients the pulmonary pressure was > or = 40 mmHg. RESULTS: Preoperatively, the PH patients were older (p < 0.001), had a lower LVEF (p = 0.001), and had a higher logistic EuroSCORE (p < 0.001) and serum creatinine level (p < 0.026) when compared to NPH patients. The PH patients showed a greater tendency to develop postoperative complications (p < 0.001). After adjusting by propensity score, the in-hospital mortality was significantly higher among PH patients (p < 0.001), while multivariate logistic regressions revealed PH as an independent predictor for in-hospital mortality (p = 0.036). The 12-, 36-, and 60-month follow up mortality rates were significantly higher in the PH group. By using a Cox logistic regression model, PH was shown to be an independent predictor for follow up mortality (p = 0.035). CONCLUSION: Pulmonary hypertension increased the morbidity and mortality in patients with a low LVEF who were undergoing cardiac surgery. Future studies may identify subgroups that may benefit from a preoperative optimization of PH and/or intra- and postoperative therapies directed at minimizing the effects of the condition.

Comparison of laparoscopy and laparotomy for endometrial cancer.

OBJECTIVE: To compare the safety and efficacy of laparoscopy and laparotomy on clinical outcomes among patients with endometrial cancer. METHODS: Eligible randomized controlled trials (RCTs) conducted between 1966 and June 2010 were analyzed by meta-analysis. RESULTS: Eight RCTs were included, with 3599 patients in total. No significant difference was observed between laparoscopy and laparotomy in overall (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.50-1.82; P=0.892), disease-free (OR, 0.96; 95% CI, 0.50-1.82; P=0.892), or cancer-related (OR, 0.90; 95% CI, 0.27-3.08; P=0.871) survival. More intraoperative complications (OR, 1.33; 95% CI, 1.03-1.73; P=0.030), fewer postoperative complications (OR, 0.59; 95% CI, 0.46-0.75; P<0.001), longer operative time (standardized mean difference [SMD], 0.80; 95% CI, 0.46-1.15; P<0.001), lower blood loss (SMD, -2.29; 95% CI, -3.67 to -0.91; P=0.001), and shorter hospital stay (SMD, -2.60; 95% CI, -3.47 to -1.72; P<0.001) were associated with laparoscopy. There was no significant difference between the groups in pelvic (SMD, 0.22; 95% CI, -0.03 to 0.48; P=0.086) or para-aortic (SMD, 0.54; 95% CI, -0.04 to 1.11; P=0.067) lymph node yield. CONCLUSION: Laparoscopy has short-term advantages and seemingly equivalent long-term outcomes and, in experienced hands, might be a feasible alternative to laparotomy for endometrial cancer.