Association of abnormal electrocardiograph metrics with prolonged recovery time in incident hemodialysis patients.

BACKGROUND: Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. METHODS: Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. RESULTS: Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0-10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. CONCLUSION: Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient's underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

Mycobacterium tuberculosis 6C sRNA binds multiple mRNA targets via C-rich loops independent of RNA chaperones.

Bacterial small regulatory RNAs (sRNAs) are the most abundant class of post-transcriptional regulators and have been well studied in Gram-negative bacteria. Little is known about the functions and mechanisms of sRNAs in high GC Gram-positive bacteria including Mycobacterium and Streptomyces. Here, we performed an in-depth study of 6C sRNA of Mycobacterium tuberculosis, which is conserved among high GC Gram-positive bacteria. Forty-seven genes were identified as possible direct targets of 6C sRNA and 15 of them were validated using an in vivo translational lacZ fusion system. We found that 6C sRNA plays a pleotropic role and regulates genes involved in various cellular processes, including DNA replication and protein secretion. Mapping the interactions of 6C sRNA with mRNA targets panD and dnaB revealed that the C-rich loops of 6C sRNA act as direct binding sites to mRNA targets. Unlike in Gram-negative bacteria where RNA binding proteins Hfq and ProQ are required, the interactions of 6C sRNA with mRNAs appear to be independent of RNA chaperones. Our findings suggest that the multiple G-C pairings between single stranded regions are sufficient to establish stable interactions between 6C sRNA and mRNA targets, providing a mechanism for sRNAs in high GC Gram-positive bacteria.

Associations of serum and dialysate electrolytes with QT interval and prolongation in incident hemodialysis: the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study.

BACKGROUND: Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients. METHODS: In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men). RESULTS: At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation. CONCLUSION: Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.

Intranasal HD-Ad-FS vaccine induces systemic and airway mucosal immunities against SARS-CoV-2 and systemic immunity against SARS-CoV-2 variants in mice and hamsters.

The outbreak of coronavirus disease 19 (COVID-19) has highlighted the demand for vaccines that are safe and effective in inducing systemic and airway mucosal immunity against the aerosol transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we developed a novel helper-dependent adenoviral vector-based COVID-19 mucosal vaccine encoding a full-length SARS-CoV-2 spike protein (HD-Ad-FS). Through intranasal immunization (single-dose and prime-boost regimens), we demonstrated that the HD-Ad-FS was immunogenic and elicited potent systemic and airway mucosal protection in BALB/c mice, transgenic ACE2 (hACE2) mice, and hamsters. We detected high titers of neutralizing antibodies (NAbs) in sera and bronchoalveolar lavages (BALs) in the vaccinated animals. High levels of spike-specific secretory IgA (sIgA) and IgG were induced in the airway of the vaccinated animals. The single-dose HD-Ad-FS elicited a strong immune response and protected animals from SARS-CoV-2 infection. In addition, the prime-boost vaccination induced cross-reactive serum NAbs against variants of concern (VOCs; Beta, Delta, and Omicron). After challenge, VOC infectious viral particles were at undetectable or minimal levels in the lower airway. Our findings highlight the potential of airway delivery of HD-Ad-FS as a safe and effective vaccine platform for generating mucosal protection against SARS-CoV-2 and its VOCs.

Intranasal HD-Ad vaccine protects the upper and lower respiratory tracts of hACE2 mice against SARS-CoV-2.

BACKGROUND: The ongoing COVID-19 pandemic has resulted in 185 million recorded cases and over 4 million deaths worldwide. Several COVID-19 vaccines have been approved for emergency use in humans and are being used in many countries. However, all the approved vaccines are administered by intramuscular injection and this may not prevent upper airway infection or viral transmission. RESULTS: Here, we describe a novel, intranasally delivered COVID-19 vaccine based on a helper-dependent adenoviral (HD-Ad) vector. The vaccine (HD-Ad_RBD) produces a soluble secreted form of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and we show it induced robust mucosal and systemic immunity. Moreover, intranasal immunization of K18-hACE2 mice with HD-Ad_RBD using a prime-boost regimen, resulted in complete protection of the upper respiratory tract against SARS-CoV-2 infection. CONCLUSION: Our approaches provide a powerful platform for constructing highly effective vaccines targeting SARS-CoV-2 and its emerging variants.

Preclinical Progress of Subunit and Live Attenuated Mycobacterium tuberculosis Vaccines: A Review following the First in Human Efficacy Trial.

Tuberculosis (TB) is the global leading cause of death from an infectious agent with approximately 10 million new cases of TB and 1.45 million deaths in 2018. Bacille Calmette-Guérin (BCG) remains the only approved vaccine for Mycobacterium tuberculosis (M. tb, causative agent of TB), however clinical studies have shown BCG has variable effectiveness ranging from 0-80% in adults. With 1.7 billion people latently infected, it is becoming clear that vaccine regimens aimed at both post-exposure and pre-exposure to M. tb will be crucial to end the TB epidemic. The two main strategies to improve or replace BCG are subunit and live attenuated vaccines. However, following the failure of the MVA85A phase IIb trial in 2013, more varied and innovative approaches are being developed. These include recombinant BCG strains, genetically attenuated M. tb and naturally attenuated mycobacteria strains, novel methods of immunogenic antigen discovery including for hypervirulent M. tb strains, improved antigen recognition and delivery strategies, and broader selection of viral vectors. This article reviews preclinical vaccine work in the last 5 years with focus on those tested against M. tb challenge in relevant animal models.