Citations

Abstract RATIONALE: Mesenchymal progenitor cells (MPCs) in the lungs of individuals with Idiopathic Pulmonary Fibrosis (IPF) show intrinsic fibrogenic properties, possessing a distinct transcriptomic profile and maintaining fibrogenic activity, which contributes to the fibroblast population in IPF. We hypothesize that IPF MPCs are distinguished from control MPCs by a unique gene interaction network. METHODS: We analyzed bulk RNA-seq data, available on the Gene Expression Omnibus (GEO) under accession numbers GSE97038 and GSE276568. In these experiments, CD44hi MPCs were isolated through flow cytometry from mesenchymal cell lines derived from IPF patients (explanted lungs from live IPF patients after lung transplant) and control subjects (lobectomy for clinical reasons) using antibodies against CD44 and SSEA4. The pooled dataset comprises nine IPF and nine control MPC lines. We identified differentially expressed genes (DEGs) in IPF MPCs compared to controls using DESeq and performed pathway enrichment analysis on DEGs using Gene Ontology (GO). We also conducted Gene Set Enrichment Analysis (GSEA) with gene sets related to stemness, pluripotency, and self-renewal. Weighted gene co-expression network analysis (WGCNA) identified functional modules specifically associated with IPF MPCs. RESULTS: Applying an adjusted p-value threshold of 0.05, we identified 134 DEGs in IPF MPCs compared to controls. GO analysis showed significant enrichment in pathways associated with leukocyte migration, extracellular matrix organization, and cell differentiation and growth. GSEA highlighted significant enrichment in two gene sets related to stemness, with adjusted p-values of 0.002 and 0.048. Using WGCNA, we identified 16 functional modules, one of which reached significance based on an adjusted p-value threshold of 0.05 and a correlation coefficient cutoff of 0.45. This significant module demonstrated a positive correlation with IPF status (correlation coefficient of 0.69, adjusted p-value 0.0085). CONCLUSION: This study is the first to characterize a distinct gene expression profile in IPF MPCs compared to controls, highlighting enriched biological processes relevant to IPF pathogenesis. GSEA results further support the hypothesis that IPF MPCs display stem cell-like gene expression patterns, including genes associated with pluripotency and self-renewal. Additionally, we identified functional gene modules that significantly correlate with the fibrogenic properties of IPF MPCs, including hub genes that may play critical roles in promoting fibrosis in IPF. These findings deepen our understanding of IPF MPC biology and identify potential targets for future research. We plan to expand this approach by increasing the sample size to enhance statistical power, aiming to identify more robust functional modules and their highly connected hub genes.

Abstract RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by chronic and progressive decline in lung function with unknown cause. Previous economic burden of IPF estimates were based on data from 2011 or earlier. Thus, more current estimates will help inform policymaking. This study aimed to quantify the healthcare resource utilization (HCRU) and direct costs associated with IPF, overall and by payer type (commercial or Medicare Advantage Prescription Drug [MAPD] plan). METHODS: This retrospective cohort study used the Optum® Research claims database from 01/01/2016 through 12/31/2023. Adult patients with IPF (defined as ≥2 claims with IPF diagnosis code within 365 days) were identified (IPF cohort), with the date of the first IPF medical diagnosis code set as the index date. A general population without IPF (control cohort) was exact matched to the IPF cohort in 1:4 ratio, based on age group, sex, geographical region, payer type (commercial vs. MAPD), and race/ethnicity. The assigned index date for the control cohort was the same as the index date of the matched IPF patient. Continuous enrollment of 12 months before and 3 months after the index date was required for both cohorts. All-cause and respiratory-related HCRU and direct costs were compared between the cohorts during the variable follow-up period, reported as observation time-weighted per-patient-per-month (wPPPM). RESULTS: A total of 7,670 IPF patients were exact matched to 30,680 control patients. The mean age was 76 years and 59% were male. HCRU during the follow-up was significantly greater across all categories in the IPF cohort compared to control cohort (p<0.001) (Table 1). The mean (standard deviation [SD]) wPPPM all-cause total healthcare costs were nearly four times higher for the IPF cohort compared to control cohort ($4,724 [$8,368] vs. $1,197 [$2,134], p<0.001). Hospitalization costs accounted for the largest proportion of all-cause medical costs for the IPF cohort (55%), whereas ambulatory costs were the largest for the control cohort (49%). The IPF cohort had significantly higher wPPPM pharmacy costs compared to the matched control cohort ($2,289 [$3,861] vs. $321 [$1,133], p<0.001) (Table 1). Similar trends were observed in respiratory-related HCRU and costs. When stratified by payer types, the total costs were significantly higher for commercially insured patients compared to patients with MAPD plan. CONCLUSION: The study demonstrated that patients with IPF incur higher economic burden compared to those without the disease, highlighting the need for more effective treatments to reduce costly healthcare resource utilization.

Listing and transplanting patients with acute liver failure (ALF) is challenging, requiring rapid assessment of the likelihood of recovery. The availability of a large number of ALF liver explants, along with their clinical data, afforded an opportunity to retrospectively evaluate liver transplantation (LT) decision-making. We hypothesized that, with the benefit of hindsight, a small number of patients might have recovered without LT. Three hundred liver explants from ALF patients of varying etiologies who had undergone LT over 22 years in the Acute Liver Failure Study Group registry were reviewed for histopathological features and degree of necrosis by a committee of 8 hepatopathologists. A second committee of 8 experienced transplant hepatologists independently reviewed clinical data on these same 300 patients and retrospectively scored the likelihood that each patient required transplantation. Only 3 (1%) of those reviewed by the Clinical Committee were considered to “Definitely” not require liver grafting, while an additional 10 (3.3%) were deemed to “Possibly” not require transplantation (Not Likely Group, N=13). There was no difference in the degree of necrosis in explants in these groups, when compared to the remaining Likely Group, N=287 (95.6%), except in acetaminophen (APAP)-associated ALF, where the degree of necrosis was more uniformly graded as severe, correlating with the need for transplantation. Virtually every patient undergoing LT for ALF retrospectively appeared to need their transplant, based on expert clinical consensus review. Overall, there was poor correlation between clinical severity and apparent degree of necrosis seen in the 300 liver explants, except perhaps for APAP subjects.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

ABSTRACT Knowledge of Treponema pallidum subspecies pallidum ( TPA ) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols-, three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Lastly, we noted that BamA and FadL candidate ECL vaccinogens previously shown to elicit antibodies that kill treponemes during in vitro cultivation are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing selection of vaccine targets. IMPORTANCE Syphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA . Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the Grading of Recommendations, Assessment, Development and Evaluation approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.