Purpose of the Review: Permanent pacemakers (PPMs) are common cardiac implantable devices indicated for patients with bradycardia or tachycardia. Currently, PPMs include both transvenous pacemakers (TV-PM) and leadless pacemakers (L-PM). This paper reviews the existing data on L-PM technology including: a) medical aspects and indications, b) patient experience and quality of life (QOL) outcome studies, and c) recommendations for optimizing patient QOL through enhanced knowledge and shared decision-making. Recent Findings: This review includes the seven papers that report on patient-reported outcomes (PRO) in leadless pacemakers and indicate that QOL is as good, if not better, than TV-PM. Existing evidence from descriptive statistics suggests that patients with L-PM report high levels of patient acceptance and satisfaction with esthetic appearance (96%), recovery (91%), and level of physical activity (74%). Summary: Leadless pacemakers provide an attractive alternative for the indicated potential patient. The evidence demonstrates the benefits of L-PM such as a minimal implant and lack of leads. Recommendations for future research indicate that electrophysiology-specific metrics are essential and control for the common co-morbidities in the PM population are needed.

BACKGROUND Synthetic messenger RNA (mRNA) vaccines have raised concerns regarding prolonged spike protein expression, immune activation, and potential off-target effects. AIM To investigate transcriptomic alterations in individuals with new-onset adverse events or cancer following mRNA coronavirus disease 2019 vaccination. METHODS Bulk RNA sequencing was performed on peripheral blood from two patient groups: (1) Individuals with new-onset nonmalignant adverse events; and (2) Individuals newly diagnosed with cancer post-vaccination. A control group of normal individuals was used for comparison. Differential gene expression was analyzed using DESeq2, and Gene Set Enrichment Analysis was conducted using the MSigDB database and custom gene sets. RESULTS Both vaccine patient groups displayed widespread transcriptional dysregulation. In the nonmalignant adverse event group, hallmark enrichments included mitochondrial dysfunction, proteasome-mediated stress, transcriptomic instability, and systemic inflammation. The cancer group exhibited additional hallmarks of genomic instability and epigenetic reprogramming. Nonsense-mediated decay, ribosomal stress, and myelocytomatosis oncogene activation were prominent in both groups, while immune signaling via toll-like receptors and type I interferons was particularly elevated in cancer patients. The observed transcriptomic profiles indicate cellular stress responses, mitochondrial dysfunction, and immune dysregulation following exposure to mRNA vaccines, potentially in susceptible individuals. CONCLUSION Shared and distinct molecular signatures in both cohorts demonstrate underlying mechanisms contributing to post-vaccine symptomatology and complications, including oncogenesis and or progression of malignant disease. These findings underscore the need for a deeper investigation into the long-term safety of mRNA vaccines and host response variability.

Background/Objectives: Synthetic mRNA vaccines have raised concerns regarding prolonged spike protein expression, immune activation, and potential off-target effects. This study investigates transcriptomic alterations in individuals with new-onset adverse events or cancer following mRNA COVID-19 vaccination. Methods: Bulk RNA sequencing was performed on peripheral blood from two patient groups: individuals with new-onset nonmalignant adverse events and individuals newly diagnosed with cancer post-vaccination. A control group of healthy individuals was used for comparison. Differential gene expression was analyzed using DESeq2, and Gene Set Enrichment Analysis (GSEA) was conducted using the MSigDB database and custom gene sets. Results: Both vaccine patient groups displayed widespread transcriptional dysregulation. In the nonmalignant adverse event group, hallmark enrichments included mitochondrial dysfunction, proteasome-mediated stress, transcriptomic instability, and systemic inflammation. The cancer group exhibited additional hallmarks of genomic instability, and epigenetic reprogramming. Nonsense-mediated decay (NMD), ribosomal stress, and MYC activation were prominent in both groups, while immune signaling via TLRs and type I interferons was particularly elevated in cancer patients. Conclusions: The observed transcriptomic profiles indicate persistent cellular stress responses, mitochondrial dysfunction, and immune dysregulation following exposure to mRNA vaccines, potentially in susceptible individuals. Shared and distinct molecular signatures in both cohorts demonstrate underlying mechanisms contributing to post-vaccine symptomatology and complications, including oncogenesis and or progression of malignant disease. These findings underscore the need for a deeper investigation into the long-term safety of mRNA vaccines and host response variability.

Persistent SARS-CoV-2 spike protein after mRNA vaccination and after infection has been linked to a broad range of chronic pathology, yet the structural basis of that persistence is frequently described imprecisely. This analysis examines the sequence features that render spike prion-like, the intracellular processes that convert those features into destructive protein species, and the downstream consequences for transcriptional stability, host proteostasis, and tissue integrity. A critical distinction underlies this analysis: SARS-CoV-2 is a laboratory-synthesized recombinant virus, not a product of natural evolution. Its spike glycoprotein carries intrinsic prion-like domains that are present after both infection with the recombinant virus and prolonged expression from nucleoside-modified mRNA vaccines; therefore, spike is prion-like after both infection and mRNA vaccination. There is no direct evidence that intact spike is a classical self-replicating prion. The prion-like designation rests on sequence features that enable β-sheet aggregation and cross-seeding of host amyloids. Critically, once recombinant spike enters the interior of the cell, two processes become decisive determinants of pathology: (1) trafficking through the endoplasmic reticulum (ER) induces ER stress and the unfolded protein response, driving proteolytic fragmentation and release of aggregation-prone fragments; and (2) ribosomal frameshifting (programmed viral frameshifting and N1-methylpseudouridine-induced +1 frameshifting) generates aberrant, out-of-frame polypeptides. The combination of ER fragmentation and ribosomal shifts inside the cellular machinery is a critical determinant that markedly increases production of self-templating fibrous aberrant proteins. Spike elements are detected for months to years after both infection and vaccination. We have previously documented long-term (years) persistence of vaccine-derived spike, residual mRNA and plasmid elements, genomic integration events, transcriptomic and gene-expression alterations, and fatal myocarditis through joint Neo7Bioscience–McCullough Foundation surveillance. Building upon earlier work on spike-driven NF-κB activation, neuroinflammation, and proteolytic detoxification strategies, we synthesize the mechanisms by which recombinant spike initiates destructive protein formation, threatens transcriptional fidelity, and amplifies proteostatic collapse via cross-seeding. The cellular prion protein is itself a candidate target: a five-residue spike sequence (YQAGS) differs by one residue from YQRGS in its globular C-terminal domain, and a case series has reported 26 patients in whom Creutzfeldt-Jakob disease began a mean of 11.38 days after COVID-19 vaccination, on a timescale sharply compressed relative to classical sporadic disease. Cross-seeding is not restricted to neural proteins. Thioflavin T-positive amyloid microclots have been detected in every participant of a recent cohort in which 94% had received COVID-19 mRNA vaccination and no participant had laboratory-confirmed prior infection, and purified spike alone converts fibrinogen into insoluble, fibrinolysis-resistant amyloid aggregates. In parallel, multi-year surveys of 808 embalmers across five countries document large white fibrous intravascular casts in a substantial fraction of the deceased, and Raman micro-spectroscopy of representative specimens shows stage-dependent β-sheet enrichment distinct from conventional postmortem thrombi. Enzymatic dissolution combined with precision molecular intervention via patient-specific ITI-PES peptides offers a rational therapeutic approach. Taken together, these findings define persistent recombinant spike as a potent prion-like driver of proteostatic collapse, pathological cross-seeding, transcriptional instability, and progressive tissue dysfunction across multiple organ systems.