Background Neonatal cardiac surgery frequently requires thymectomy, but the consequences of extensive thymic removal remain uncertain. Methods We retrospectively studied 105 neonates undergoing sternotomy (2015–2024), comparing infections and 6‐month lymphocyte recovery after partial versus total thymectomy, with Firth regression adjusted for bypass duration and surgical era. Separate cohorts underwent paired plasma biomarker (n=8) and whole‐blood RNA sequencing (n=4) analysis before and after thymectomy. Results Among 105 neonates, 27 underwent partial and 78 total thymectomy. Multiple infections occurred in 2 of 27 (7%) after partial and 23 of 78 (30%) after total thymectomy (P=0.02); after adjustment for bypass duration and surgical era, the association was not statistically significant (Firth‐adjusted odds ratio, 2.99 [95% CI, 0.82–15.85]; P=0.10). Median lymphocyte count decreased after total but increased after partial thymectomy (change, −0.8 versus +0.9×10 3 /μL; P=0.011). Tumor necrosis factor‐α decreased in all 8 biomarker participants (unadjusted P=0.0078). RNA sequencing in 4 patients (2 partial, 2 total thymectomy) identified 835 differentially expressed genes; pre–T‐cell receptor α decreased in all 4 pairs (log2 fold change, −2.50; adjusted P=6×10 ‐6 ). Conclusions Total thymectomy was associated with reduced 6‐month lymphocyte recovery and higher unadjusted odds of multiple infections. The infection association was not statistically significant after adjustment, and few events (2 of 27 after partial thymectomy) limit precision and cannot exclude a clinically important effect; these findings are hypothesis‐generating. Biomarker and transcriptomic findings are exploratory and cannot distinguish thymectomy from surgery, maturation, or postoperative recovery. Prospective studies are underway to evaluate thymic preservation and autologous reimplantation.
Background Hypertension affects over 1.3 billion adults worldwide, and poor adherence to daily oral therapy contributes to inadequate blood pressure (BP) control. We characterized BPR‐30901649, a liver‐targeted small interfering RNA (siRNA) against angiotensinogen (AGT), hypothesizing that its optimized design would confer greater potency and durability than an advanced clinical‐stage AGT siRNA benchmark. Methods BPR‐30901649 was selected through in vitro and in vivo screening in HepG2 cells and human AGT (hAGT) transgenic mice. Off‐target risk was assessed by RNA sequencing in primary human hepatocytes. Pharmacodynamics were evaluated in hAGT mice after single and repeat subcutaneous (SC) dosing, and in hypertensive cynomolgus monkeys given a single SC dose of 1.5 or 3.0 mg/kg, with serum AGT and systolic BP (SBP) monitored for 20 weeks. Investigational New Drug (IND)‐enabling toxicology was conducted in rats and nonhuman primates (NHPs). Results RNA sequencing indicated low off‐target risk. In hAGT mice, BPR‐30901649 produced significantly deeper serum AGT knockdown than the benchmark. In hypertensive NHPs, a single SC injection produced rapid, dose‐dependent, and sustained AGT suppression; at week 20, SBP remained reduced by 14.2% (20.3 mm Hg) and 17.3% (25.3 mm Hg) in the low‐ and high‐dose groups, respectively. In repeat‐dose toxicology, the no‐observed‐adverse‐effect level was 100 mg/kg in NHPs. Conclusions BPR‐30901649 surpassed an advanced clinical‐stage AGT siRNA benchmark in vivo and showed a wide preclinical safety margin, supporting its clinical development as a potential twice‐yearly therapy for hypertension.
Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, life‐threatening condition. Timely and accurate diagnosis remains a challenge. We assessed time from first recorded clinical manifestation to ATTR‐CM diagnosis in the United States and characterized manifestations associated with diagnostic delays. Methods Retrospective analysis of US claims data (Komodo Healthcare Map, July 1, 2016–June 30, 2024). Patients were required to have ≥3 years of continuous enrollment before diagnosis. Results Among 7509 patients, mean age 75.9 years, 63.2% male, 54.5% White, and 28.6% Black. Patients had a median of 8 manifestations before diagnosis; median observed time from first recorded manifestation to diagnosis was 5.2 years, shorter for variant versus wild‐type ATTR‐CM (4.4 versus 5.2 years). Within 3 years before diagnosis, patients had a mean of 12.04 (95% CI, 11.75–12.35) primary care physician visits and 14.45 (95% CI, 14.10–14.80) specialists of interest visits, most commonly with cardiologists and ophthalmologists. In adjusted analyses, variant ATTR‐CM was associated with shorter time to diagnosis (β, −0.41 years [95% CI, −0.56 to −0.26]), whereas comorbidities, including hypertension (β, 0.46 years [95% CI, 0.27–0.64]), were associated with longer delays. Conclusions The diagnostic trajectory for ATTR‐CM can be prolonged and challenging, leading to more advanced disease at diagnosis and increased burden. Raising awareness may provide an opportunity for earlier diagnosis.
