COVID-19 vaccine-associated myocarditis.

Myocarditis is now recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccination, particularly in adolescent and young adult males. Since the authorization of the Pfizer-BioNTech™ and Moderna™ mRNA vaccines targeting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein, the Centers for Disease Control and Prevention (CDC) has reported 1175 confirmed cases of myocarditis after COVID-19 vaccination in individuals ages 30 years and younger as of January 2022. According to CDC data in June 2021, the incidence of vaccine-mediated myocarditis in males ages 12-29 years old was estimated to be 40.6 cases per million second doses of COVID-19 mRNA vaccination administered. Individuals with cases of COVID-19 vaccine-mediated myocarditis typically present with acute chest pain and elevated serum troponin levels, often within one week of receiving the second dose of mRNA COVID-19 vaccination. Most cases follow a benign clinical course with prompt resolution of symptoms. Proposed mechanisms of COVID-19 vaccine myocarditis include molecular mimicry between SARS-CoV-2 spike protein and self-antigens and the triggering of preexisting dysregulated immune pathways in predisposed individuals. The higher incidence of COVID-19 vaccine myocarditis in young males may be explained by testosterone and its role in modulating the immune response in myocarditis. There is limited data on long-term outcomes in these cases given the recency of their occurrence. The CDC continues to recommend COVID-19 vaccination for everyone 5 years of age and older given the greater risk of serious complications related to natural COVID-19 infection including hospitalization, multisystem organ dysfunction, and death. Further study is needed to better understand the immunopathology and long-term outcomes behind COVID-19 mRNA vaccine-mediated myocarditis.

Association of intermittent versus continuous hemodialysis modalities with mortality in the setting of acute stroke among patients with end-stage renal disease.

Patients with end-stage renal disease (ESRD) are 8-10 times more likely to suffer from a stroke compared with the general public. Despite this risk, there are minimal data elucidating which hemodialysis modality is best for patients with ESRD following a stroke, and guidelines for their management are lacking. We retrospectively queried the US Renal Data System administrative database for all-cause mortality in ESRD stroke patients who received either intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT). Acute ischemic stroke and hemorrhagic stroke were identified using the International Classification of Diseases 9th Revision (ICD-9)/ICD-10 codes, and hemodialysis modality was determined using Healthcare Common Procedure Coding System (HCPCS) codes. Time to death from the first stroke diagnosis was the outcome of interest. Cox proportional hazards modeling was used, and associations were expressed as adjusted HRs. From the inclusion cohort of 87,910 patients, 92.9% of patients received IHD while 7.1% of patients received CRRT. After controlling for age, race, sex, ethnicity, and common stroke risk factors such as hypertension, diabetes, tobacco use, atrial fibrillation, and hyperlipidemia, those who were placed on CRRT within 7 days of a stroke had an increased risk of death compared with those placed on IHD (HR=1.28, 95% CI 1.25 to 1.32). It is possible that ESRD stroke patients who received CRRT are more critically ill. However, even when the cohort was limited to only those patients in the intensive care unit and additional risk factors for mortality were controlled for, CRRT was still associated with an increased risk of death (HR=1.32, 95% CI 1.27 to 1.37). Therefore, further prospective clinical trials are warranted to address these findings.

Protein Isoprenylation in Yeast Targets COOH-Terminal Sequences Not Adhering to the CaaX Consensus.

Protein isoprenylation targets a subset of COOH-terminal Cxxx tetrapeptide sequences that has been operationally defined as a CaaX motif. The specificity of the farnesyl transferase toward each of the possible 8000 combinations of Cxxx sequences, however, remains largely unresolved. In part, it has been difficult to consolidate results stemming from in vitro and in silico approaches that yield a wider array of prenylatable sequences relative to those known in vivo We have investigated whether this disconnect results from the multistep complexity of post-translational modification that occurs in vivo to CaaX proteins. For example, the Ras GTPases undergo isoprenylation followed by additional proteolysis and carboxymethylation events at the COOH-terminus. By contrast, Saccharomyces cerevisiae Hsp40 Ydj1p is isoprenylated but not subject to additional modification. In fact, additional modifications are detrimental to Ydj1p activity in vivo We have taken advantage of the properties of Ydj1p and a Ydj1p-dependent growth assay to identify sequences that permit Ydj1p isoprenylation in vivo while simultaneously selecting against nonprenylatable and more extensively modified sequences. The recovered sequences are largely nonoverlapping with those previously identified using an in vivo Ras-based yeast reporter. Moreover, most of the sequences are not readily predicted as isoprenylation targets by existing prediction algorithms. Our results reveal that the yeast CaaX-type prenyltransferases can utilize a range of sequence combinations that extend beyond the traditional constraints for CaaX proteins, which implies that more proteins may be isoprenylated than previously considered.