Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.
Introduction A high incidence of mortality and severe COVID‐19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID‐19 pandemic; however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID‐19 vaccinations in subsequent pandemic waves may modify COVID‐19 disease severity and mortality in this immunocompromised population. We describe COVID‐19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS‐CoV‐2 delta and omicron variants. Methods We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS‐CoV‐2 from May 2021 to May 2022. Descriptive statistics were reported; the chi‐square test was utilized to identify factors associated with 90‐day all‐cause mortality and severity of COVID‐19 infection. Results Over the 1‐year study period, 77 HSCT recipients at our center contracted COVID‐19 (43 allogenic; 34 autologous). Twenty‐six (33.8%) patients were infected with the SARS‐CoV‐2 delta variant, while 51 (66.2%) had the SARS‐CoV‐2 omicron variant. Thirty‐nine (50.6%) patients required hospitalization. More than 80% had received prior COVID‐19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID‐19 infection was associated with increased odds of mortality [odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20–40]. The 90‐day all‐cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01–0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01–0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10–23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89–75.4) were associated with greater severity of COVID‐19 infection. Conclusion We observed favorable outcomes with COVID‐19 infection in a cohort of vaccinated HSCT patients. The SARS‐CoV‐2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID‐19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID‐19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS‐CoV‐2 variants also remains important in this immunocompromised population.
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