Citations

Background: C-type natriuretic peptide (CNP) is of endothelial cell origin and represents the most potent anti-fibrotic peptide of the natriuretic peptide family and is important for extracellular matrix homeostasis including mediating bone growth in the young. Cardiorenal aging is associated with altered cardiac and renal structure and function that may contribute to the development of heart and kidney failure, particularly in the elderly. The impact of aging on circulating CNP and associated changes in cardiorenal structure and function are undefined. Hypothesis: We hypothesized that a decrease in endogenous plasma CNP occurs with aging and is associated with an increase in cardiorenal fibrosis and altered left ventricular (LV) and renal structure and function. Methods: Studies were performed in 2, 11 and 20 month old male Fischer rats (n = 8 –10/group). Echo was used to assess LV structure and function. Blood pressure (BP), urinary protein excretion, plasma B-type natriuretic peptide (BNP) and CNP were measured. Kidneys and LV were harvested for gross and histology analysis. Mean±SE, *p<0.05. Results: Aging from 2 to 20 months was associated with progressive reductions in plasma CNP (30±3 to 21±1* to 9±1*pg/ml). Significant and progressive cardiac and renal fibrosis were observed with aging (LV: 9±0.3 to 15±0.7* to 21±1*% and kidney: 1±0.3 to 8±2* to 17±1* %). In contrast to CNP, plasma BNP was modestly increased from the 2 to 20 month old group (21±2 to 26±1*pg/ml). The reduction in CNP and increase in BNP, the latter a biomarker for LV dysfunction, were associated with decreased EF (88±1 to 80±1*%) and increased LVEDd (6.61±0.09 to 7.48±0.09*mm). BP and urinary protein excretion were mildly elevated with aging (91±1 to 101±3* mmHg and 8±0.3 to 20±3* mg/day, respectively). Conclusion: We report for the first time that aging is associated with a progressive decline in circulating CNP and progressive cardiorenal fibrosis, systolic dysfunction and proteinuria. Further studies are warranted to explore the hypothesis that a mechanism of cardiorenal aging with altered cardiorenal structure and function may include a decrease in the bioavailability of CNP.

Brain arteriovenous malformations (bAVMs) are complex, and rare arteriovenous shunts that present with a wide range of signs and symptoms, with intracerebral hemorrhage being the most severe. Despite prior societal position statements, there is no consensus on the management of these lesions. ARISE (Aneurysm/bAVM/cSDH Roundtable Discussion With Industry and Stroke Experts) was convened to discuss evidence-based approaches and enhance our understanding of these complex lesions. ARISE identified the need to develop scales to predict the risk of rupture of bAVMs, and the use of common data elements to perform prospective registries and clinical studies. Additionally, the group underscored the need for comprehensive patient management with specialized centers with expertise in cranial and spinal microsurgery, neurological endovascular surgery, and stereotactic radiosurgery. The collection of prospective multicenter data and gross specimens was deemed essential for improving bAVM characterization, genetic evaluation, and phenotyping. Finally, bAVMs should be managed within a multidisciplinary framework, with clinical studies and research conducted collaboratively across multiple centers, harnessing the collective expertise and centralization of resources.

Abstract Introduction Several studies have shown a positive association between Obstructive Sleep Apnea (OSA) and malignancies such as lung cancer. However, the effects of intermittent hypoxemia in cancer-free survival following curative therapy are not known. We propose that OSA-related episodic hypoxemia and hypoxic burden are independent risk factors for accelerated lung cancer reoccurrence (&lt; 2 years). Methods We performed a retrospective record review of patients 18 years and older from January 2016 to September 2023 with history of non-small cell lung cancer who received an overnight oximetry study (OXY) within three years prior to undergoing curative malignancy treatment. Subjects with history of central sleep apnea, baseline oxygen saturation (SpO2) below 90%, receiving supplemental oxygen or treatment for OSA were excluded. Results 403 patients met inclusion criteria (52% female vs 48% males; median age 74 y). The most common histologic subtypes were adenocarcinoma (68%) followed by squamous cell carcinoma (22%). Most patients fell into Stage IA1 (35%) followed by IA2 (24.1%) and IB (19%) as per TNM 8th edition classification. Over this period, 68 patients (22%) had lung cancer recurrence (median 19 months). A 4% oxygen desaturation index (ODI) of &gt;15 and time spent in desaturation events were found to be a risk factor for cancer reappearance in less than 2 years (p&lt; 0.001). Measures of hypoxic burden such as time spent below 89% SpO2, average SpO2 value below 89%, and single nadir oxygen levels, showed a similar association (p&lt; 0.001). This was irrespective of histologic subtype, stage at diagnosis, and all studied demographic variables. Basal SpO2 demonstrated no correlation. A multivariate proportional hazard survival model showed that ODI&gt;15 was no longer significant, however average SpO2 below 89% and single minimum oxygen level remained strongly correlated with accelerated recurrence. Conclusion This study showed a strong, positive association between accelerated lung cancer recurrence and OSA-related episodic hypoxemia and hypoxic burden on our univariate analysis. The multivariate model demonstrated correlation with hypoxic load measures only, suggesting the need for a larger sample to elucidate the involvement of this highly treatable risk factor. To our knowledge, this is the first study revealing this potential link. Support (if any)

ABSTRACT Background and hypothesis The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health-care payers. Methods A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health-care payer with a lifetime time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced-cost biosimilar rituximab. Results Rituximab for the treatment of membranous nephropathy was cost effective (assuming a willingness-to-pay threshold of $50 000 per quality-adjusted life year (QALY) gained; in $US 2021) compared with cyclosporine, with an ICER of $8373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was $28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favorable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. Conclusions Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.

Abstract Rationale It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between −600 and −250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97–6.0; and RR per 4 μg ⋅ m−3 PM2.5, 1.43; 95% CI, 0.93–2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0–2.7). Conclusions Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene–environment interactions may influence prevalence of interstitial lung features in COPD.

Abstract Background Pancreatic cysts (PC) are increasingly detected through abdominal imaging, prompting exploration of alternatives such as endoscopic ultrasound-guided pancreatic cyst ablation (EUS-PCA) due to the risks and costs associated with surgery. This study conducts a systematic review and meta-analysis of EUS-PCA's short-term efficacy and complications for PC management. Methods A systematic review and meta-analysis were carried out on PubMed, Ovid, Cochrane, and TRIP electronic databases. The primary outcome was cyst resolution (partial and complete) and persistence on imaging 12 months after ablation. The secondary outcome was procedure-related adverse events. Results Eight studies were eligible for analysis. Complete cyst resolution on imaging 12 months after EUS ablation was 50% [95% CI 36, 63, I2 = 85.31%]. Partial cyst resolution was 27% [95% CI 15, 41, I2 = 87.07%], and cyst persistence was 17% [95% CI 11, 24, I2 = 62.11%]. The rate of complete resolution varied depending on the treatment agent (for ethanol 29% [95% CI 10, 53], lauromacrogol 51% [95% Cl 36, 67], ethanol and paclitaxel 63% [95% CI 48, 76], paclitaxel and gemcitabine 67% [95% CI 45, 83], ethanol, paclitaxel and gemcitabine 61% [95% CI 39, 80]). Post-procedure adverse events included abdominal pain in 4% [95% CI 0, 11], pancreatitis in 3% [95% CI 1, 5], and fever in 1% [95% CI 0, 3] of all patients. Conclusion The treatment of pancreatic cysts with EUS ablation results in acceptable levels of complete resolution, and low incidence of severe adverse events. The effectiveness of this treatment is further enhanced when chemoablative agents are employed.

Abstract Rationale Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n = 1,367) versus above 4,000 ft (1,219 m) elevation (n = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (−32.3 m [95% confidence interval, −49.8 to −14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George’s Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT 01969344).