Dissecting antibodies induced by a chimeric yellow fever-dengue, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in naive and dengue-exposed individuals

Sanofi Pasteur has developed a chimeric yellow fever–dengue, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is currently approved for use in several countries. In clinical trials, CYD-TDV was efficacious at reducing laboratory-confirmed cases of dengue disease. Efficacy varied by dengue virus (DENV) serotype and prevaccination dengue immune status. We compared the properties of antibodies in naive and DENV-exposed individuals who received CYD-TDV. We depleted specific populations of DENV-reactive antibodies from immune serum samples to estimate the contribution of serotype-cross-reactive and type-specific antibodies to neutralization. Subjects with no preexisting immunity to DENV developed neutralizing antibodies to all 4 serotypes of DENV. Further analysis demonstrated that DENV4 was mainly neutralized by type-specific antibodies whereas DENV1, DENV2, and DENV3 were mainly neutralized by serotype cross-reactive antibodies. When subjects with preexisting immunity to DENV were vaccinated, they developed higher levels of neutralizing antibodies than naive subjects who were vaccinated. In preimmune subjects, CYD-TDV boosted cross-reactive neutralizing antibodies while maintaining type-specific neutralizing antibodies acquired before vaccination. Our results demonstrate that the quality of neutralizing antibodies induced by CYD-TDV varies depending on DENV serotype and previous immune status. We discuss the implications of these results for understanding vaccine efficacy

Analyzing the Human Serum Antibody Responses to a Live Attenuated Tetravalent Dengue Vaccine Candidate

BACKGROUND: Dengue virus serotypes 1-4 (DENV-1-4) are the most common vector-borne viral pathogens of humans and the etiological agents of dengue fever and dengue hemorrhagic syndrome. A live-attenuated tetravalent dengue vaccine (TDV) developed by Takeda Vaccines has recently progressed to phase 3 safety and efficacy evaluation. METHODS: We analyzed the qualitative features of the neutralizing antibody (nAb) response induced in naive and DENV-immune individuals after TDV administration. Using DENV-specific human monoclonal antibodies (mAbs) and recombinant DENV displaying different serotype-specific Ab epitopes, we mapped the specificity of TDV-induced nAbs against DENV-1-3. RESULTS: Nearly all subjects had high levels of DENV-2-specific nAbs directed to epitopes centered on domain III of the envelope protein. In some individuals, the vaccine induced nAbs that tracked with a DENV-1-specific neutralizing epitope centered on domain I of the envelope protein. The vaccine induced binding Abs directed to a DENV-3 type-specific neutralizing epitope, but findings of mapping of DENV-3 type-specific nAbs were inconclusive. CONCLUSION: Here we provide qualitative measures of the magnitude and epitope specificity of the nAb responses to TDV. This information will be useful for understanding the performance of TDV in clinical trials and for identifying correlates of protective immunity

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effect of adrenomedullin gene delivery on insulin resistance in type 2 diabetic rats

AbstractType 2 diabetes mellitus is one of the common metabolic disorders that ultimately afflicts large number of individuals. Adrenomedullin (AM) is a potent vasodilator peptide; previous studies reported development of insulin resistance in aged AM deficient mice. In this study, we employed a gene delivery approach to explore its potential role in insulin resistance. Four groups were included: control, diabetic, non-diabetic injected with the AM gene and diabetic injected with the AM gene. One week following gene delivery, serum glucose, insulin, triglycerides, leptin, adiponectin and corticosterone were measured as well as the insulin resistance index (HOMA-IR). Soleus muscle glucose uptake and RT-PCR of both AM and glucose transporter-4 (GLUT 4) gene expressions were assessed. A single tail vein injection of adrenomedullin gene in type 2 diabetic rats improved skeletal muscle insulin responsiveness with significant improvement of soleus muscle glucose uptake, HOMA-IR, serum glucose, insulin and triglycerides and significant increase in muscle GLUT 4 gene expression (P<0.05) compared with the non-injected diabetic rats. The beneficial effects of AM gene delivery were accompanied by a significant increase in the serum level of adiponectin (2.95±0.09 versus 2.33±0.17μg/ml in the non-injected diabetic group) as well as a significant decrease in leptin and corticosterone levels (7.51±0.51 and 262.88±10.34 versus 10.63±1.4 and 275.86±11.19ng/ml respectively in the non-injected diabetic group). The conclusion of the study is that AM gene delivery can improve insulin resistance and may have significant therapeutic applications in type 2 diabetes mellitus

Significant beat-to-beat variability of E/e' irrespective of respiration

The E/e' ratio is commonly used in Doppler echocardiographic examinations to estimate the pulmonary capillary wedge pressure. The rationale of using this ratio is to combine left ventricular (LV) filling (E) and relaxation (e') velocities to indirectly assess left atrial pressure. However, the accuracy of this index has recently been questioned, particularly in patients with controlled heart failure1. Likewise, the potential beat-to-beat variability of such measurements remains undetermined. The cardiovascular system is subject to several oscillations with the potential of influencing LV function and its intra-cavitary pressures, hence measurements of its filling and relaxation velocities. The aim of this pilot study was to assess the beatto-beat variability of the E/e' ratio in one minute long examination in healthy subjects, and patients with various severity of amyloid heart disease. The results show that despite critical application of the standard echocardiographic recording recommendations, E/e' beat-to-beat variability was 36 % (22 to 50%) in healthy subjects and 17 % (11-26%) in patients, and where the most severe amyloid heart disease had the least variability. Thus, clinical use of a single or few cardiac beats might not necessarily reflect an accurate ratio between the two velocities, and hence casts doubt over their diagnostic value

Right ventricular involvement in transthyretin amyloidosis

Background: The extent of right ventricular (RV) involvement in transthyretin amyloidosis (ATTR) is unknown.Objectives: This study sought to establish the degree of RV involvement in ATTR amyloidosis, and compare findings with RV involvement in hypertrophic cardiomyopathy (HCM).Methods: Forty-two patients with ATTR amyloidosis and echocardiographic evidence of cardiac amyloidosis (cardiac ATTR), 19 ATTR patients with normal left ventricular (LV) wall thickness (non-cardiac ATTR), 25 patients with diagnosed HCM and 30 healthy controls were included in this study. Echocardiographic measurements for conventional parameters, as well as RV global and segmental strain, were recorded.Results: When comparing RV structure and function between cardiac ATTR amyloidosis and HCM patients, only segmental strain differed between the two groups. In cardiac ATTR amyloidosis, we found an RV apex-to-base strain gradient with highest deformation in the apex. This pattern was reversed in patients with HCM.Conclusions: RV involvement is common in cardiac ATTR patients. The present study also detected an RV apical sparing pattern in patients with ATTR cardiomyopathy, similar to what has previously been described for the left ventricle in these patients. This pattern was not seen in HCM patients. Further studies are needed to assess the clinical importance of these findings

Early effect of surgical revascularisation on left ventricular twist function

Aim: The direct effect of coronary artery bypass graft (CABG) surgery on early recovery of myocardial function, particularly twist and rotation is not well studied. The aim is to assess the early response of the 3 myocardial components, circumferential, longitudinal and oblique to CABG in a group of patients with isolated coronary disease. Methods: We studied 14 patients, age 64±10 years, before CABG and before hospital discharge using various Doppler echocardiographic techniques including speckle tracking imaging, and compared them with 28 age and gender matched controls. Results Before surgery: Compared to controls, patients had significantly reduced left ventricular ejection fraction (LVEF) (p=0.01) but maintained stroke volume (SV) (p=0.5). Diastolic left ventricular (LV) function indices were statistically abnormal (p=0.01). LV lateral wall long axis amplitude of motion and myocardial systolic velocities were both reduced (p=0.01) as was septal amplitude of motion (p=0.05). LV peak global longitudinal strain (GLS) was reduced as were systolic (GLSRs) and early diastolic (GLSRe) global longitudinal strain rates (p=0.01 for all). LV peak basal and apical rotations, twist and torsion were not different. Q-peak basal rotation was shorter than controls (p=0.01). After surgery: None of these measurements changed except peak GLS which further reduced (p=0.01). Pre-operatively, SV correlated with global LV function: twist (r= -0.65, p=0.01), and LV torsion (r=-0.66, p=0.01) but LVEF did not correlate with either. Post-operatively, SV correlated with E/A ratio (r=0.66, p=0.01), and the time interval Q- peak basal rotation rate (r=0.8, p=0.002). LVEF correlated with the time interval Q- peak LV twist (r=0.6, p=0.04). Conclusion CABG does not result in significant early detectable segmental LV functional improvement along any of its three myocardial components, but stroke volume becomes dependent on early basal rotation and filling pressures

Reduced left atrial myocardial deformation irrespective of cavity size : a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis

BACKGROUND: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement. OBJECTIVES: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR). METHODS: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness &gt;12 mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24 hour Holter monitoring to determine the presence of atrial arrhythmia. RESULTS: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (β = 3.28, p = .012). CONCLUSION: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e' and LV deformation, is also a strong predictor for atrial arrhythmic events