Citations

The pathogenesis of asthma in elderly is not well understood. Using a mouse model of asthma, we show that aging results in decreased lung function and less responsiveness to allergen exposure, impacted by locally produced brain-derived neurotrophic factor. Aging also decreases allergen-induced inflammation but increases airway remodeling and senescence. Our results suggest that senescence pathways may contribute to asthma pathogenesis in elderly.

Abstract Objectives Social support (SS) and social isolation (SI) are social determinants of health (SDOH) associated with psychiatric outcomes. In electronic health records (EHRs), individual-level SS/SI is typically documented in narrative clinical notes rather than as structured coded data. Natural language processing (NLP) algorithms can automate the otherwise labor-intensive process of extraction of such information. Materials and Methods Psychiatric encounter notes from Mount Sinai Health System (MSHS, n = 300) and Weill Cornell Medicine (WCM, n = 225) were annotated to create a gold-standard corpus. A rule-based system (RBS) involving lexicons and a large language model (LLM) using FLAN-T5-XL were developed to identify mentions of SS and SI and their subcategories (eg, social network, instrumental support, and loneliness). Results For extracting SS/SI, the RBS obtained higher macroaveraged F1-scores than the LLM at both MSHS (0.89 versus 0.65) and WCM (0.85 versus 0.82). For extracting the subcategories, the RBS also outperformed the LLM at both MSHS (0.90 versus 0.62) and WCM (0.82 versus 0.81). Discussion and Conclusion Unexpectedly, the RBS outperformed the LLMs across all metrics. An intensive review demonstrates that this finding is due to the divergent approach taken by the RBS and LLM. The RBS was designed and refined to follow the same specific rules as the gold-standard annotations. Conversely, the LLM was more inclusive with categorization and conformed to common English-language understanding. Both approaches offer advantages, although additional replication studies are warranted.

Key Points PIEZO1 activation reduces cystogenesis: Yoda1 activates PIEZO1, raising calcium and lowering cAMP, reducing cyst growth in autosomal dominant polycystic kidney disease models. Context-dependent role of PIEZO1: PIEZO1 knockout in mice with or without polycystic kidneys does not affect cyst formation, suggesting redundancy in mechanosensitive pathways. Therapeutic potential: Findings support PIEZO1 activation as a part of combination therapy to slow cyst growth in autosomal dominant polycystic kidney disease, needing more in vivo studies. Background The disruption of calcium signaling associated with polycystin deficiency is a key factor in abnormal epithelial growth in autosomal dominant polycystic kidney disease. Calcium homeostasis can be influenced by mechanotransduction. The mechanosensitive cation channel PIEZO1 has been implicated in sensing intrarenal pressure and regulating urinary osmoregulation, but its role in kidney cystogenesis is unclear. Methods We hypothesized that altered mechanotransduction contributes to cystogenesis in autosomal dominant polycystic kidney disease and that activation of mechanosensitive cation channels could be a therapeutic strategy. Results We demonstrate that Yoda1, a PIEZO1 activator, increases intracellular calcium and reduces forskolin-induced cAMP levels in mouse inner medullary collecting duct (mIMCD3) cells. Notably, knockout of polycystin-2 attenuated the efficacy of Yoda1 in reducing cAMP levels in mIMCD3 cells. Yoda1 also reduced forskolin-induced mIMCD3 cyst surface area in vitro and cystic index in mouse metanephros ex vivo in a dose-dependent manner. However, collecting duct–specific PIEZO1 knockout neither induced cystogenesis in wild-type mice nor altered cystogenesis in the Pkd1 RC/RC mouse model. Conclusions These findings support the potential role of PIEZO1 agonists in mitigating cystogenesis by increasing intracellular calcium and reducing cAMP levels, but the unaltered in vivo cystic phenotype after PIEZO1 knockout in the collecting duct suggests possible redundancy in mechanotransductive pathways.

Our previous study suggests that glial-derived neurotrophic factor (GDNF) is involved in allergen-induced airway hyperreactivity and remodeling in vivo. Here, we show that GDNF has no direct effects in remodeling of human airway smooth muscle (ASM) but GDNF dysregulates mitochondrial morphology in human ASM in the context of asthma.

Loeys-Dietz syndrome (LDS) has been associated with multiple vascular abnormalities involving the entire arterial tree. However, limited reports regarding compromise in the aortoiliac and femoral bifurcation are available. Further, recommendations for optimal approach, thresholds for diameter at the time of surgery, and surveillance are also limited. We present a case of a 67-year-old male patient with LDS and aneurysmal aortoiliac and enlarging common femoral arteries aneurysms, who underwent open surgical repair. His past surgical history included multiple vascular interventions for lower extremity claudication and bilateral hip replacements. The right hip arthroplasty was previously removed due to infection. From the vascular standpoint, the patient underwent staged endovascular left hypogastric artery embolization and open aorto-bi-profunda bypass with a Rifampin-soaked Dacron graft. At 5-month follow-up, he remains asymptomatic with healed incisions and patent bypasses. This case highlights the challenges in managing peripheral aneurysms in LDS patients, emphasizing the need for tailored treatment strategies. While open repair is preferred, endovascular options may be considered in selected cases. Surveillance remains critical with annual cross-sectional imaging. Surgical planning is intricate due to comorbidities, anatomical complexities, and previous surgical infection. Surveillance of these patients must be strict as multiple vascular and non-vascular complications may arise. Therefore, collaborative decision-making is essential for optimal outcomes in this known high-risk population with connective tissue disorders.