Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation.

Conditioning intensity contributes significantly to outcomes in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated two myeloablative conditioning dosing ranges of intravenous (IV) busulfan (Bu) in combination with fludarabine in 70 patients. In 2015, our practice changed to target busulfan area under the curve (AUC) of ≥ 19.7 mg*h/L. We assessed responses in patients receiving busulfan AUCs of < 19.7 mg*h/L (Low-Bu) and ≥ 19.7 mg*h/L (High-Bu). At 18-month median follow-up, no differences in overall survival (OS) and relapse-free survival (RFS) were found between Low-Bu and High-Bu groups (p = 0.35 and p = 0.29, respectively). Relapses occurred in 25.7% of patients. No differences in median time to relapse were noted. Minimal residual disease (MRD)-positive patients had a shorter median OS and RFS than MRD-negative patients. No differences were found in OS and RFS between Low-Bu and High-Bu groups in MRD-positive patients (p = 0.86 and p = 0.83, respectively), or MRD-negative patients (p = 0.56 and p = 0.38, respectively). Non-relapsed mortality (NRM) at 100 days was 3.4% vs. 4.1% in the Low-Bu vs. High-Bu groups. There were no significant differences in the incidence of acute-graft-versus-host disease (aGVHD) (71.4% vs. 63.4%) or chronic GVHD (cGVHD) (48.3% vs. 43.9%) between the groups. The cumulative incidence of grades III-IV aGVHD was 24.1% in Low-Bu group and 22.4% in High-Bu group. In conclusion, targeting a busulfan AUC of > 19.7 mg*h/L with fludarabine does not appear to add an advantage in OS and RFS.

Transcranial direct current stimulation for post-stroke dysphagia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated as a tool for dysphagia recovery after stroke in several single-center randomized controlled trials (RCT). OBJECTIVE: The aim of this investigation was to quantitatively evaluate the effect of tDCS on dysphagia recovery after a stroke utilizing a systematic review and meta-analysis. METHODS: Major databases were searched through October 2019 using a pre-defined set of criteria. Any RCT investigating the efficacy of tDCS in post-stroke dysphagia using a standardized dysphagia scale as outcome measure was included. Studies were assessed for risk of bias and quality using the Physiotherapy Evidence Database (PEDro) scale. Effect sizes were calculated from extracted data and entered into a random effects analysis to obtain pooled estimates of the effect. RESULTS: Seven RCTs with a total sample size of 217 patients fulfilled the criteria and were included in the analysis. The overall results revealed a small but statistically significant pooled effect size (0.31; CI 0.03, 0.59; p = 0.03). The subgroup which explored the stimulation intensity yielded a moderately significant effect size for the low-intensity stimulation group (g = 0.44; CI = 0.08, 0.81 vs. g = 0.15, CI - 0.30, 0.61). For the other subgroup analyses, neither comparisons of affected vs. unaffected hemisphere or acute vs. chronic stroke phase revealed a significant result. CONCLUSION: This meta-analysis demonstrates a modest but significant beneficial effect of tDCS on improving post-stroke dysphagia. Whether benefits from this intervention are more pronounced in certain patient subgroups and with specific stimulation protocols requires further investigation.

Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-analysis.

OBJECTIVES: This study sought to perform a systematic review and meta-analysis to understand the role of stress cardiac magnetic resonance imaging (CMR) in assessing cardiovascular prognosis in patients with known or suspected coronary artery disease (CAD). BACKGROUND: Although stress CMR is excellent for the diagnosis of obstructive CAD, the prognostic value of stress CMR has been less well described. METHODS: PubMed, Cochrane CENTRAL, and metaRegister of Controlled Trials were searched for stress CMR studies with >6 months of prognostic data. Primary endpoints were cardiovascular death, myocardial infarction (MI), and a composite outcome of cardiovascular death or MI during follow-up. Summary effect estimates were generated with random-effects modeling, and annualized event rates were assessed. RESULTS: Nineteen studies (14 vasodilator, 4 dobutamine, and 1 that used both) involved a total of 11,636 patients with a mean follow-up of 32 months. Patients had a mean age of 63 ± 12 years, 63% were male, and 26% had previous MI; mean left ventricular ejection fraction was 61 ± 12%; and late gadolinium enhancement was present in 29% and ischemia in 32%. Patients with ischemia had a higher incidence of MI (odds ratio [OR]: 7.7; p < 0.0001), cardiovascular death (OR: 7.0; p < 0.0001), and the combined endpoint (OR: 6.5; p < 0.0001) compared with those with a negative study. The combined outcome annualized events rates were 4.9% for a positive versus 0.8% for a negative stress CMR (p < 0.0001), 2.8% versus 0.3% for cardiovascular death (p < 0.0001), and 2.6% versus 0.4% for MI (p < 0.0005). The presence of late gadolinium enhancement was also significantly associated with a worse prognosis. CONCLUSIONS: A negative stress CMR study is associated with very low risk of cardiovascular death and MI. Stress CMR has excellent prognostic characteristics and may help guide risk stratification of patients with known or suspected CAD.

Apolipoprotein E2 accentuates postprandial inflammation and diet-induced obesity to promote hyperinsulinemia in mice.

Genetic studies have revealed the association between the ε2 allele of the apolipoprotein E (apoE) gene and greater risk of metabolic diseases. This study compared C57BL/6 mice in which the endogenous mouse gene has been replaced by the human APOE2 or APOE3 gene (APOE2 and APOE3 mice) to identify the mechanism underlying the relationship between ε2 and obesity and diabetes. In comparison with APOE3 mice, the APOE2 mice had elevated fasting plasma lipid and insulin levels and displayed prolonged postprandial hyperlipidemia accompanied by increased granulocyte number and inflammation 2 h after being fed a lipid-rich meal. In comparison with APOE3 mice, the APOE2 mice also showed increased adiposity when maintained on a Western-type, high-fat, high-cholesterol diet. Adipose tissue dysfunction with increased macrophage infiltration, abundant crown-like structures, and inflammation were also observed in adipose tissues of APOE2 mice. The severe adipocyte dysfunction and tissue inflammation corresponded with the robust hyperinsulinemia observed in APOE2 mice after being fed the Western-type diet. Taken together, these data showed that impaired plasma clearance of apoE2-containing, triglyceride-rich lipoproteins promotes lipid redistribution to neutrophils and adipocytes to accentuate inflammation and adiposity, thereby accelerating the development of hyperinsulinemia that will ultimately lead to advanced metabolic diseases.