Citations

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21 + cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21 + cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21 + cell clearance did not alter bone loss due to aging; conversely, p16 + cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21 + neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21 + OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell–like OCH subset that was p21 + and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of p21 + versus p16 + senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

Abstract Rationale Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Background: Bystander CPR (BCPR) strongly influences survival from OHCA yet is provided in a minority of cases. The AHA has promulgated guidelines on provision of pre-arrival Hands-Only dispatcher-assisted telephone CPR (TCPR) instructions to increase the proportion of arrests receiving early BCPR; however, the impact of those guidelines is unknown. Objective: Evaluate the impact of implementing the TCPR guidelines on: recognition of OHCA by 911 dispatchers, time from call receipt to start of TCPR instructions, time to first chest compression (CC), prehospital ROSC, survival, and favorable neuro outcome (FNO). Methods: Dispatch audio records of OHCA in 3 large dispatch centers in Arizona (10/10-3/13) were reviewed using a standardized time-stamp methodology. Data were entered into a structured TCPR database linked to EMS and hospital outcome data. Intervention: Implementation of a 3.5-hour staff training and a guideline-based change in dispatch protocol. Results: There were 860 pre-implementation (P1) and 799 post-implementation (P2) cases. A total of 1265 cases met inclusion criteria. Outcome data collection and linkage is ongoing: ROSC, survival and neuro outcomes were available in 26%, 24% and 22% of cases, respectively. The proportion of cases receiving TCPR increased: P1 (28.7%); P2 (49.9%, p<0.001). Median time to beginning TCPR instructions decreased significantly: P1 (153 sec); P2 (129 sec, p<0.001) as did median time to first CC: P1 (198 sec); P2 (162 sec, p<0.001). Outcomes - see Table. Conclusion: The implementation of the AHA pre-arrival TCPR guidelines was associated with a significant improvement in the time-to-CPR instructions and time-to-first CCs and rate of provision of telephone-assisted bystander CPR. This small, preliminary analysis of prehospital ROSC, survival, and FNO revealed higher, but statistically non-significant, rates after the interventions.

Introduction: Atrial Fibrillation (AF) is an important contributor to insufficient left ventricular pacing and mortality in patients undergoing cardiac resynchronization therapy (CRT). The incidence and prevalence of AF post-CRT implant, in patients with and without previous history of AF, has not previously been described. Hypothesis: AF prevalence in CRT patients, despite history of AF, is higher than previously understood. Methods: Subjects implanted with a CRT-Defibrillator (CRT-D) enrolled in the PainFree SST study and with device data collection were analyzed. Subjects who exited within 30 days of implant, had < 27 days of available daily AT/AF burden data, or had ≥ 10% of daily AT/AF data missing were excluded. We defined incidence and prevalence of clinically meaningful device documented AF using previously published criteria (≥1 day with AF > 6 hours). History of AF at enrollment was documented based on clinical history. Results: The analysis included 944 patients (68±11 years; 78% male, EF 28±9%, QRS 152±29 ms; 59% NYHA III/IV). The duration from implant to study exit or death was 2.0 ± 0.8 years (IQR 1.5-2.5). History of AT/AF was documented in 37% of patients at baseline. Overall, any AT/AF was found in 85.2 % of subjects during follow-up. Clinically meaningful AT/AF was found in 30.3% of subjects. Of the 345 subjects with history of AF at baseline, 51.9% had clinically meaningful AT/AF during follow-up vs.17.9% for subjects without known AF (p<0.0001). 24.8% of subjects experienced at least one day of ≥ 23h of AT/AF. 6.9% of subjects had ≥ 23h of AT/AF for > 95% of days with data. Conclusions: AF occurs in a substantial proportion of CRT-D patients and clinically documented history of AF prior to CRT-D implant corresponds poorly with device documented AT/AF during follow-up. Device documented AF should be evaluated in CRT-D patients with and without previous history of AF to individualize strategies to maximize left ventricular pacing and minimize disruption due to AF.