Citations

Abstract Background. Sarcopenia (i.e. skeletal muscle loss) is a significant contributor to adverse clinical outcomes in patients with COPD. Nutritional intake and physical activity influence sarcopenia and frailty. There is increasing recognition that social determinants of health (SDOH) play critical roles in nutritional status. We evaluated the impact of SDOH on clinical outcomes in hospitalized patients with COPD and sarcopenia and/or frailty. Design. The Nationwide Inpatient Sample (NIS) (years 2018-2020) was analyzed to study adult hospitalized patients with a primary diagnosis of COPD (J43, J44). SDOH was defined by ICD-10 Z-codes as a composite sum of problems related to housing and economic status, unemployment, occupation, psychosocial, family, and healthcare access. Sarcopenia and frailty were defined by a composite of ICD10 codes that have been previously validated in the literature. Multivariate regression models were generated to determine the impact of sarcopenia, frailty, and sarcopenia+frailty on clinical outcomes in COPD patients, which were adjusted for age, race, sex, SDOH, and comorbidities (cardiovascular disease, anemia, coagulopathy, HIV, depression, diabetes mellitus). Results. Of the 282,164 COPD patients that were analyzed, 7254 (2.6%) had codes related to SDOH, 21,035 (7.5%) had sarcopenia, 106,995 (37.9%) had frailty, and 11,293 (4%) had both sarcopenia and frailty. The predominant SDOH code was related to housing (70.9%) followed by social environment (11.5%). SDOH codes were more prevalent in patients with sarcopenia alone (3.6%), compared with frailty (2.5%) or sarcopenia+frailty (2.6%) (p<0.001). When adjusted for demographics including age, race, and sex, SDOH was associated with greater odds of sarcopenia (adj OR 1.64, 95% CI: 1.51-1.79), frailty (adj OR 1.17, 95% CI: 1.11-1.24), and sarcopenia+frailty (adj OR 1.72; 95% CI: 1.54-1.90). COPD patients with sarcopenia+frailty had the greatest association with adverse clinical outcomes (i.e. in-hospital mortality, higher healthcare cost, and higher length of stay), followed by frailty alone, and sarcopenia alone (Table 1). Conclusion. In COPD patients, SDOH increased the odds for a diagnosis of sarcopenia, frailty, and sarcopenia+frailty. Sarcopenia+frailty had the greatest association with adverse outcomes in COPD patients, followed by frailty alone, and sarcopenia alone.

Abstract RATIONALE The best described endotype of COPD is alpha-1 antitrypsin (AAT) deficiency, which is due to a genetic abnormality in the SERPINA1 gene. Homozygotes for the Z allele (PI[asterisk]ZZ individuals) carry the genotype most commonly associated with severe AAT deficiency, but a highly prevalent endotype is the heterozygous state (PI[asterisk]MZ individuals). Here we test the hypothesis that individuals with PI[asterisk]MZ genotype are at higher risk for COPD exacerbation and healthcare utilization compared to those with no pathogenic variants in the SERPINA1 gene (PI[asterisk]MM individuals). METHODS Real-world data on 4,456 individuals with available AAT genotyping were extracted from the Cleveland Clinic Health System (CCHS) electronic health records (EHR) and analyzed to compare the risk of moderate COPD exacerbation (defined as a short-term steroid prescription), all-cause emergent care (defined as an express care visit, urgent care visit, or emergency department visit), and all-cause hospitalization between individuals with PI[asterisk]MZ vs. PI[asterisk]MM genotypes. Cox proportional hazards models were used to adjust for age, sex, race, BMI, smoking status, comorbidity count, liver disease diagnosis, and median income by zip code.To assess the effect of AAT levels on outcomes, we categorized participants into three groups based on AAT level and used 90 mg/dL as a threshold given it is the lower limit of the normal reference range and genotype: MM individuals with an AAT level >90 mg/dL, MZ >90 mg/dL and MZ <90 mg/dL. To assess the effect of PI[asterisk]MZ genotype among individuals with pre-existing lung disease, we performed a subgroup analysis of individuals with at least a six-month inhaler prescription. RESULTS In this cohort, 308 individuals had a PI[asterisk]MZ genotype. PI[asterisk]MZ was associated with increased risk for moderate COPD exacerbations (adjusted HR [95% CI]: 1.66 [1.27, 2.17]) and hospitalizations (adjusted HR [95% CI]: 1.44 [1.19, 1.75]) compared to PI[asterisk]MM. The risk of hospitalization was higher among PI[asterisk]MZ individuals with AAT levels <90 mg/dL (adjusted HR [95% CI]: 1.59 [1.14, 2.23]) but not in those with AAT levels >90 mg/dL, as compared to PI[asterisk]MM. Sensitivity analysis in those treated with inhaler therapy showed overall similar results. CONCLUSIONS Increased hospitalizations and moderate COPD exacerbations among PI[asterisk]MZ individuals compared to PI[asterisk]MM individuals merit future prospective studies to better characterize the longitudinal course and healthcare utilization among those with an PI[asterisk]MZ genotype. Given the high prevalence of these carriers globally, PI[asterisk]MZ represents a COPD phenotype that invites additional investigation to identify biomarkers of worse disease and treatable traits.

ObjectiveThe objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis.MethodsThe Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation.ResultsWe present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus‐based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3–5 years for those achieving complete renal response.ConclusionThis guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.

Objectives: To determine associations between physician sex and use of postoperative healthcare resources among patients undergoing common surgeries in Ontario, Canada. Background: Prior studies have shown that patients of female physicians experience better outcomes and have lower healthcare costs compared with patients of male physicians. Understanding differences in resource utilization may offer insights into the care pathways and practice patterns contributing to these differences. Methods: We conducted a population-based, retrospective cohort study of adults (≥18 years of age) undergoing 1 of 25 common surgeries, between January 1, 2007, and December 31, 2019, in Ontario, Canada. The primary outcome was the utilization of one of the following: intensive care unit admission, other medical interventions (eg, tracheostomy, new dialysis starts, and home oxygen), and discharge care needs (eg inpatient rehab, long-term care, and home care use) within 30 days. The data were summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: This population-based study included 1,100,193 patients (61.8% female). Patients treated by male surgeons had higher use of postoperative resources versus those with female surgeons within 30 days (adjusted rate 33.1; 95% confidence interval [CI]: 28.0–39.2 versus 31.2; 95% CI: 25.8–37.7), 90 days, and 1 year. Consistent with these findings, following adjustment for patient, surgeon, procedural, and hospital characteristics, patients treated by male surgeons were significantly more likely to utilize postoperative resources within 30 days (adjusted odds ratio: 1.14; 95% CI: 1.03–1.27; P = 0.010) and at other time points. This difference was primarily driven by the higher use of home care among patients with a male versus female surgeon at all time points (30 days: adjusted odds ratio, 1.13; 95% CI: 1.05–1.21; P = 0.002). Conclusions: Patients with male surgeons had higher postoperative resource utilization when compared with those treated by female surgeons, which was almost entirely driven by the higher use of home care. Further mixed-methods investigation is needed to better understand other potentially relevant factors including surgical outcomes, individual patient preferences, and surgical team decision-making.

Abstract Porous nanofibrous microspheres (PNMs) present a versatile and minimally invasive strategy for tissue regeneration, combining biomimetic morphology, tunable structure, and injectability. While self‐assembly and co‐axial electrospray are explored for PNM fabrication, these methods are limited in compositional versatility and production scalability. Here, a 3D‐printed microfluidic platform is presented that enables large‐scale fabrication of PNMs with precise control over size, pore architecture, and morphology. PNMs can be functionalized with bioactive molecules through UV crosslinking, enhancing their regenerative potential by promoting osteogenesis in human bone marrow stromal cells (hBMSCs), angiogenesis in human umbilical vein endothelial cells (HUVECs), and exerting anti‐inflammatory effects on macrophages. Subcutaneous implantation in rats demonstrates that PNMs support cell infiltration, minimize fibrosis, and facilitate tissue integration, achieving complete cell penetration and tissue incorporation within 14 days. These findings establish PNMs as versatile, scalable, and customizable platforms, ideal for applications as injectable drugs or cell carriers, as well as powders, offering promising solutions for wound healing and tissue regeneration.

ABSTRACT Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5’ RNA ligase-mediated rapid amplification of cDNA ends (5’ Repeat-RLM-RACE), we identified novel C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, novel intronic template transcripts – even those with short (32 nucleotide) leaders – exhibited robust expression compared to exon-intron and repeat-containing lariat reporters. To assess endogenous lariat repeat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intronic-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development. SIGNIFICANCE STATEMENT An intronic GGGGCC repeat expansion in C9orf72 supports an unusual translational initiation process known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat (DPR) proteins that contribute to neurodegeneration in ALS and FTD. How an intronic repeat RNA engages with ribosomes to support such translation is unclear. Here we identify a series of novel mRNA transcripts that initiate within the repeat-containing intron to create linear m 7 G-capped templates for RAN translation from GGGGCC repeats. These cryptic mRNAs are present in patient iNeurons, engage with ribosomes, and robustly support RAN translation. This finding has important implications for both our understanding of the mechanism by which RAN translation occurs and on therapeutic development in this currently untreatable class of neurodegenerative disorders.

Abstract Objective In utero fetal spina bifida repair decreases the risk for cerebrospinal fluid (CSF) diversion including ventriculoperitoneal (VP) shunt placement, reverses hindbrain herniation, and improves motor function with a higher likelihood of independent ambulation. Unfortunately, in utero surgery can be complicated by preterm delivery. The goal of this study was to compare pregnancy and neonatal outcomes between individuals who delivered very preterm, and those who delivered later in gestation following in utero spina bifida repair. Methods Data from the North American Fetal Therapy Network Fetal Myelomeningocele Consortium Registry collected from 2011 to 2024 were analyzed. Three cohorts of patients were categorized by gestational age at delivery and compared: <30 weeks, 30–34 weeks, and >34 weeks. Comparisons between groups for maternal and delivery outcomes were completed for the entire cohort and then analyzed for those with available CSF diversion data up to 1 year of life. Chi‐square or Fisher's exact tests were used to compare categorical variables, and Kruskal–Wallis tests were used to determine if there are significant differences between the distributions of the three groups. A p ‐value <0.05 was considered significant. Results A total of 1213 patients were analyzed (<30 weeks, n = 111 [9.2%]; 30–34 weeks, n = 323 [26.6%]; >34 weeks, n = 779 [64.2%]). Overall fetal and neonatal mortality was 2.2%, 85% of which occurred in the <30‐week cohort, where perinatal mortality was 21%. Latency from fetal surgery to delivery averaged 2.1 weeks for the <30‐week group. Rates of abruption, chorioamnionitis, and spontaneous labor were higher in the <30‐week group compared to later gestational age cohorts. Neonatal morbidity was also significantly higher in the <30‐week cohort for sepsis, apnea, respiratory distress, patent ductus arteriosus, intraventricular hemorrhage, and periventricular leukomalacia in the <30‐week cohort. CSF diversion data were available for 677 neonates (<30 weeks, n = 53; 30–34 weeks, n = 186; >34 weeks, n = 438). There was no significant difference in VP shunt placement between the different gestational age groups. Conclusion Very preterm birth following in utero spina bifida repair results in significant perinatal mortality and neonatal morbidity. Delivery prior to 30 weeks of gestation occurs in 9% of patients after in utero spina bifida repair, resulting in a 21% perinatal mortality rate. However, even among those who delivered very preterm, a reduction in VP shunt rates, a benefit of in utero repair, appears to be preserved. Further data are warranted to assess the impact of prematurity following in utero surgery on ambulation and developmental outcomes.