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ABSTRACT Background The impact of sex in the clinical presentation and outcomes of patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) has not been studied, particularly in patients with severe kidney involvement at presentation (eGFR < 15 ml/min/1.73 m2). Methods A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and eGFR<15 ml/min/1.73 m2 or end-stage kidney disease (ESKD) at presentation. Clinical presentation and renal outcomes were analyzed according to sex. Results We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR < 15 ml/min/1.7 3m2 at the time of diagnosis: 78 (47%) were females and 88 (53%) were males. Hypertension was more frequently present in males (85.2% vs 70.5%, P = .022). Median serum creatinine (SCr) was higher in males when compared with females [5.2 (IQR 4.2–7.4) vs 3.6 (IQR 2.8–5.1) mg/dl, P < .001]. Males started dialysis within 4 weeks more frequently than female (p = .003) although the median percentage of crescents was similar between groups (35.7% in males versus 36.4% in females, P = .0873). However, the rate of dialysis initiation or progression to ESKD in the first 12 months was not different between males (15, 62.5%) versus females (29, 61.7%) at 12 months. By multivariable logistic regression, factors related with dialysis initiation within the first 4 weeks in our cohort were SCr, alveolar hemorrhage, and PR3-ANCA adjusted for sex. Conclusion In our cohort, male patients presented with higher serum creatinine (SCr), and dialysis was started within the first 4 weeks more frequently (53.4% vs 30.7%). There were no differences in outcomes of kidney recovery, overall dialysis rates, and progression to ESKD within 12 months in patients with AAV-GN and eGFR < 15 ml/min/1.73 m2 between groups.

Selective inhibition of the more than 100 S1 family serine proteases is a long-standing challenge due to their active site similarity. Mesotrypsin, implicated in cancer progression, exemplifies these difficulties; no current inhibitors achieve selectivity over other human trypsins. We found an unexpected autoinhibited conformation of mesotrypsin via x-ray crystallography, revealing a cryptic pocket adjacent to the active site. Using high-throughput virtual screening targeting this cryptic pocket, we identified a conformationally selective small-molecule inhibitor that stabilizes the inactive state of mesotrypsin. This inhibitor demonstrates selectivity for mesotrypsin over other trypsins. Our findings challenge the accepted view of digestive trypsins as constitutively active enzymes lacking potential for allosteric regulation. Furthermore, analyses of other structures suggest that dynamic sampling of closed states with analogous allosteric cryptic pockets appears widespread among S1 serine proteases. These observations point to a potentially generalizable strategy to achieve selective inhibition, offering broad implications for drug development targeting serine proteases in cancer and other diseases.

ABSTRACTIntroductionEsophageal dysmotility following metabolic bariatric surgery (MBS) may relate to decreased gastric compliance. We investigated high‐resolution esophageal manometry (HRM) and secondary peristalsis assessed by functional lumen imaging probe (FLIP) and their association with intragastric pressure after MBS.MethodsPatients undergoing HRM, FLIP, and barium esophagram (BE) after MBS were included. HRM metrics and proximal intragastric pressure at baseline (IGP baseline), during wet swallow‐induced esophagogastric junction relaxation (IGP EGJ opening), and following wet swallow‐induced esophagogastric junction opening with subsequent closure (IGP post EGJ closure) were measured. Contractile response was assessed during FLIP.ResultsForty patients (26 Roux en Y gastric bypass, 14 sleeve gastrectomy) with FLIP a median of 4 years after MBS, were identified. HRM was normal or consistent with ineffective esophageal motility (IEM) in 33 (82.5%) patients, while the contractile response on FLIP was abnormal (disordered/impaired, absent, or spastic reactive) in 28 (70%). Delayed emptying on BE was numerically more frequent with abnormal FLIP (6% vs. 0%, p = 0.08). IGP post‐EGJ closure (median 21.8 vs. 15 mmHg, p = 0.03) and ∆ IGP post‐EGJ closure—IGP baseline (median 4 vs. 0 mmHg, p = 0.02) were greater and predictive of abnormal contractility on FLIP (OR 1.11, 95% CI 1.00–1.2, p = 0.03 and OR 1.6, 95% CI 1.07–2.39, p = 0.003, respectively).DiscussionAbnormal contractility on FLIP, reflecting disordered secondary peristalsis, frequently occurs despite normal HRM findings after MBS. Secondary peristalsis may be associated with reduced gastric compliance, reflected by elevated proximal intragastric pressure. FLIP contractility could serve as an early marker for post‐MBS esophageal dysfunction.

Abstract Rationale: Airway-stenosing disease is a significant clinical problem in multiple populations. While the immediate endoscopic and clinical response to bronchoscopic interventions are high, rates of clinically significant recurrence are elevated, and often require multiple and frequent reinterventions. Newer strategies to prevent recurrence of central and proximal airway stenosis are needed. Methods: Retrospective review of bronchoscopic balloon bronchoplasties performed at the Mayo Clinic utilizing paclitaxel coated balloons (PCB) in 2023-2024 for recurrent airway stenosis. IN.PACT Admiral and AV balloons (sizes 5-12 mm, 3.5 mcg/mm2 paclitaxel dose) were used with an inflation time of 2-3 minutes. Procedural success was defined as <50% airway stenosis or resolution of the procedural indication. Reintervention was considered only if a therapeutic bronchoscopy was subsequently required to address the same lesion treated with PCB. Only patients with follow-ups >90 days were included in the reintervention inter-procedural time analysis. Results: Thirty-three procedures were performed in 18 patients. Seventeen (51%) for lung transplantation-associated stenosis (29% anastomotic/perianastomotic, 76% lobar and segmental stenoses), 8 (24%) for granulomatous polyangiitis-associated stenosis, 3 for postintubation tracheal stenosis and 2 for chemical/pill injury. Eighteen cases (54%) utilized an additional dilation modality (12 non-coated balloon dilation, 4 rigid dilation), 5 spray cryotherapy, 6 other ablative therapies (4 CO2-laser, 2 electrocautery cuts), and 6 received an airway stent during the same procedure. 57% percent of interventions occurred in the lobar, 27% mainstem/bronchus intermedius, 9% tracheal, 7% segmental airways. Thirty-one (93%) cases had a satisfactory initial endoscopic result. The median number of bronchoscopic therapeutic interventions required before the use pf PCB was 5 (IQR 2.5-11.5), which significantly decreased to 0.1 (IQR 0-1, range 0-9) after PCB (p <0.001). The reintervention-free survival significantly increased after PCB dilation from a median 35 days (IQR 28.7-80.5) to 132 days (IQR 64-197; p=0.004). Twenty-one cases required subsequent bronchoscopies, sixteen (76%) of which demonstrated improvement in lesion severity when compared to the results of prior interventions. Only 16 (48%) required therapeutically addressing the same lesion. Only 2 minor complications occurred (6%, self-limited bleeding and unplanned admission), none related to paclitaxel use. Six-month mortality was 3% from an unrelated cause. Conclusions: The locoregional antiproliferative effects of paclitaxel show promise in preventing recurrence, minimizing the need for repeat procedures, and extending intervals between interventions in patients with recurrent, predominantly benign airway stenosis. Its use is feasible, safe, and future research is warranted, particularly comparing PCB with the currently available strategies.

Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems’ requirements that could enhance and accelerate the integration of these platforms.

ABSTRACTThe incidence of ischemic cholangiopathy (IC) is expected to remain significant due to rising rates of transplants performed with livers donated after circulatory death (DCD), despite the use of machine perfusion. Absent established pharmacologic interventions against this progressive etiology of allograft dysfunction and failure, we describe the use of fenofibrate—a cheap and widely‐accessible peroxisome proliferator‐activated receptor agonist that downregulates bile acid production—to impede IC progression in 15 DCD liver recipients who were not responding to reactive, standard‐of‐care management. All patients were undergoing serial endoscopic retrograde cholangiopathy (ERC) to maintain biliary patency but demonstrated progressive cholestasis, with serum alkaline phosphatase (ALP) rising 70.3% over the 90 days preceding fenofibrate. Cholestasis improved in all patients after fenofibrate initiation, with a 63.9% reduction in mean ALP at 90 days, maintained at 270 days (p = 0.02) and 360 days (p = 0.06). ALP improvement was associated with reduced ERC frequency during and after fenofibrate treatment, and this improvement was independent of concurrent ERC or ursodeoxycholic acid use during fenofibrate treatment. In patients who stopped treatment, ALP increased. No fenofibrate‐associated adverse events were seen. These preliminary data support the further study of agents that downregulate bile acid production as a means of impeding IC in DCD livers.

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.