• An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice.

      Nanishi, Etsuro; Borriello, Francesco; O'Meara, Timothy R; McGrath, Marisa E; Saito, Yoshine; Haupt, Robert E; Seo, Hyuk-Soo; van Haren, Simon D; Cavazzoni, Cecilia B; Brook, Byron; et al. (American Association for the Advancement of Science, 2022-01-26)
      Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
    • Prediction of Incident Heart Failure in CKD: The CRIC Study

      Zelnick, Leila R.; Shlipak, Michael G.; Soliman, Elsayed Z.; Anderson, Amanda; Christenson, Robert; Kansal, Mayank; Deo, Rajat; He, Jiang; Jaar, Bernard G.; Weir, Matthew R.; et al. (Elsevier, 2022-01-01)
      Introduction: Heart failure (HF) is common in chronic kidney disease (CKD); identifying patients with CKD at high risk for HF may guide clinical care. We assessed the prognostic value of cardiac biomarkers and echocardiographic variables for 10-year HF prediction compared with a published clinical HF prediction equation in a cohort of participants with CKD. Methods: We studied 2147 Chronic Renal Insufficiency Cohort (CRIC) participants without prior HF with complete clinical, cardiac biomarker (N-terminal brain natriuretic peptide [NT-proBNP] and high sensitivity troponin-T [hsTnT]), and echocardiographic data (left ventricular mass [LVM] and left ventricular ejection fraction [LVEF] data). We compared the discrimination of the 11-variable Atherosclerosis Risk in Communities (ARIC) HF prediction equation with LVM, LVEF, hsTnT, and NT-proBNP to predict 10-year risk of hospitalization for HF using a Fine and Gray modeling approach. We separately evaluated prediction of HF with preserved and reduced LVEF (LVEF ≥50% and <50%, respectively). We assessed discrimination with internally valid C-indices using 10-fold cross-validation. Results: Participants’ mean (SD) age was 59 (11) years, 53% were men, 43% were Black, and mean (SD) estimated glomerular filtration rate (eGFR) was 44 (16) ml/min per 1.73 m2. A total of 324 incident HF hospitalizations occurred during median (interquartile range) 10.0 (5.7–10.0) years of follow-up. The ARIC HF model with clinical variables had a C-index of 0.68. Echocardiographic variables predicted HF (C-index 0.70) comparably to the published ARIC HF model, while NT-proBNP and hsTnT together (C-index 0.73) had significantly better discrimination (P = 0.004). A model including cardiac biomarkers, echocardiographic variables, and clinical variables had a C-index of 0.77. Discrimination of HF with preserved LVEF was lower than for HF with reduced LVEF for most models. Conclusion: The ARIC HF prediction model for 10-year HF risk had modest discrimination among adults with CKD. NT-proBNP and hsTnT discriminated better than the ARIC HF model and at least as well as a model with echocardiographic variables. HF clinical prediction models tailored to adults with CKD are needed. Until then, measurement of NT-proBNP and hsTnT may be a low-burden approach to predicting HF in this population, as they offer moderate discrimination.
    • Time-specific associations of wearable sensor-based cardiovascular and behavioral readouts with disease phenotypes in the outpatient setting of the Chronic Renal Insufficiency Cohort.

      Lahens, Nicholas F; Rahman, Mahboob; Cohen, Jordana B; Cohen, Debbie L; Chen, Jing; Weir, Matthew R; Feldman, Harold I; Grant, Gregory R; Townsend, Raymond R; Skarke, Carsten; et al. (SAGE Publications Inc., 2022-06-16)
      Patients with chronic kidney disease are at risk of developing cardiovascular disease. To facilitate out-of-clinic evaluation, we piloted wearable device-based analysis of heart rate variability and behavioral readouts in patients with chronic kidney disease from the Chronic Renal Insufficiency Cohort and controls (n  =  49). Time-specific partitioning of heart rate variability readouts confirm higher parasympathetic nervous activity during the night (mean RR at night 14.4  ±  1.9 ms vs. 12.8  ±  2.1 ms during active hours; n  =  47, analysis of variance (ANOVA) q  =  0.001). The α2 long-term fluctuations in the detrended fluctuation analysis, a parameter predictive of cardiovascular mortality, significantly differentiated between diabetic and nondiabetic patients (prominent at night with 0.58  ±  0.2 vs. 0.45  ±  0.12, respectively, adj. p  =  0.004). Both diabetic and nondiabetic chronic kidney disease patients showed loss of rhythmic organization compared to controls, with diabetic chronic kidney disease patients exhibiting deconsolidation of peak phases between their activity and standard deviation of interbeat intervals rhythms (mean phase difference chronic kidney disease 8.3 h, chronic kidney disease/type 2 diabetes mellitus 4 h, controls 6.8 h). This work provides a roadmap toward deriving actionable clinical insights from the data collected by wearable devices outside of highly controlled clinical environments.
    • Urinary exosome-based androgen receptor-variant 7 detection in metastatic castration-resistant prostate cancer patients

      Wang, Chao; Liu, Xiang; Li, Hongyan; Zhao, Libo; Kong, Guanyi; Chen, Jing; Li, Zhi; Qi, Jianfei; Tian, Ye; Zhang, Fengbo (AME Publishing Company, 2022-02-01)
      Background: Androgen receptor variant 7 (AR-V7) detection provides important information for the clinical management of abiraterone in metastatic castration-resistant prostate cancer (mCRPC). We performed a non-invasive urine-derived exosomal AR-V7 analysis of mCRPC patients. Methods: A total of 34 mCRPC patients were recruited including 16 patients treated with abiraterone (ABI) with stable prostate-specific antigen (PSA)/radiograph response (the ABI-Sta group) and 18 were resistant to abiraterone (the ABI-Res group). Urine was collected from patients and healthy control patients for the analysis. Exosomal ribonucleic acid was isolated from urine. Urinary exosome-based androgen receptor-variant 7 was detected by quantitative real-time polymerase chain reaction assay. Characteristics of patients and survival data were collected. The correlation between AR-V7 expression and the therapeutic effect/ survival outcomes of abiraterone was analyzed. Results: Urine is the ideal biological sample for exosome separation and AR full-length analysis. Positive urine-derived exosomal AR-V7 was detected in 32.4% (11 of 34) of the mCRPC patients’ urine samples. Positive AR-V7 was more common in the ABI-Res patients than the ABI-Sta patients (50.0% vs. 12.5%, respectively; P=0.009), and was associated with a higher PSA progression rate and poorer overall survival (OS) (P=0.0031, and P=0.0012, respectively). Conclusions: The present study showed that the detection of urine-derived exosomal AR-V7 provides a sensitive and feasible clinical workflow. The predicting role of urine-derived exosomal AR-V7 in mCRPC patients should be further verified using studies with greater sample sizes.