Citations

Objective The aim of this study was to compare infection‐related hospitalization risk among patients with nonrenal systemic lupus erythematosus initiating commonly used immunosuppressants. Methods We emulated a target trial using Optum Labs Data Warehouse claims to compare the risk of infection‐related hospitalization among patients initiating azathioprine, belimumab, methotrexate, or mycophenolic acid analogues (MPAAs) between March 2011 and September 2023. We excluded patients with prior lupus nephritis, solid‐organ or bone marrow transplantation, or rituximab/cyclophosphamide exposure. The primary outcome was time to first infection‐related hospitalization using intention‐to‐treat (ITT) and per‐protocol (PP) analyses. We applied inverse probability of treatment weighting to account for baseline covariates and fitted marginal structural Cox models incorporating time‐varying monthly glucocorticoid dose during follow‐up. Results Among 6,168 patients, 24‐month cumulative incidence of infection‐related hospitalization was 10% (95% confidence interval [CI] 8–12) for azathioprine, 8% (95% CI 5–10) for belimumab, 10% (95% CI 8–11) for methotrexate, and 13% (95% CI 10–15) for MPAAs. In ITT analyses, MPAAs had higher risk than belimumab (hazard ratio [HR] 1.55, 95% CI 1.07–2.25) and methotrexate (HR 1.32, 95% CI 1.04–1.68). In PP analyses, azathioprine (HR 2.04, 95% CI 1.01–4.16) and MPAAs (HR 2.27, 95% CI 1.11–4.62) had higher risk compared with belimumab. After accounting for time‐varying monthly glucocorticoid dose, between‐treatment differences were no longer significant. Conclusion Initial differences in the infection‐related hospitalization risk were attenuated after accounting for time‐varying glucocorticoid exposure. These findings highlight glucocorticoid exposure as an important factor associated with serious infection risk while recognizing that postbaseline glucocorticoid use may reflect both evolving disease activity and a pathway through which therapies influence infection risk. image

Background Menopause-related symptoms are common but undertreated. Digital tools that support symptom assessment and patient education may improve engagement. Objective To assess whether a previsit digital menopause symptom assessment and education tool increased treatment initiation and patient engagement compared to an educational pamphlet. Design Women aged 45–55 years with upcoming primary care appointments were invited to participate. Those with a total Menopause Rating Scale (MRS) score ≥5 indicating bothersome menopause symptoms were included. Participants were randomized to a digital menopause symptom assessment tool or a digital educational pamphlet and completed a post-visit survey (NCT06919887). Participants Of the 14,726 women invited to participate between May 12, 2025, and December 5, 2025, there were 653 (4.4%) enrolled that met eligibility criteria. Interventions Randomized to an mHealth app called emmii or a standard digital menopause educational pamphlet. Main measures Menopause treatment initiation within 30 days of the clinical visit was assessed by electronic health data. Baseline and post-visit surveys were collected assessing patient experience, engagement, and perceived usefulness. Rates of menopause hormone therapy (HT) prescribing were compared with a reference population of nonparticipants aged 45–55 who had a primary care appointment at Mayo Clinic during the same period and received no study education materials. Key results Of 653 participants enrolled and randomized, 383 completed both the baseline and post-surveys (171 intervention and 212 control). HT initiation among study participants was significantly higher than in the reference population of women (9.3% vs. 4.4%, p < 0.001). There was no difference in HT initiation between the intervention (9.1%) and control groups (9.6%) ( p = 0.83). Initiation rates were 3.8% and 4.5%, respectively ( p = 0.64) for nonhormone therapies. Conclusions Among women with bothersome menopause symptoms, those who underwent previsit symptom screening and received educational materials had higher rates of HT initiation than women who did not participate in the study. These findings suggest that structured menopause education may improve recognition and management of menopause symptoms in routine clinical practice.

Purpose: Depression is prevalent yet frequently underdiagnosed. Although speech-based detection methods show promise, most prior studies have emphasized binary classification in nontonal languages. This study examined whether acoustic features of spontaneous Mandarin speech reflect depression as a categorical condition or a continuous, dimensional construct. Method: A validated emotional Mandarin speech corpus paired with self-reported depression severity scores was analyzed. Acoustic features were extracted using the extended Geneva Minimalistic Acoustic Parameter Set. A multistage analytic framework was applied, including random forest classification to distinguish depressed from nondepressed clips, linear mixed-effects modeling to examine group and severity effects, and unsupervised clustering to examine latent structure in the acoustic feature space. Results: The random forest classifier achieved an accuracy of 72.3% and an area under the receiver operating characteristic curve of 0.826 on the held-out test set. Model performance favored sensitivity over precision in identifying depressed clips. SHapley Additive exPlanations analysis identified features across multiple acoustic domains, including spectral, pitch-related, voice quality, cepstral, and intensity measures, as important contributors to model predictions. Among the Top 10 features, no acoustic features showed statistically significant group differences. In contrast, median and mean fundamental frequencies were significantly positively associated with depression severity. Clustering analysis revealed overlapping group structures and a continuous distribution of severity scores across clusters. Conclusions: These findings provide preliminary support for a dimensional conceptualization of depression in spontaneous Mandarin speech. While classification models can distinguish depressed from nondepressed speech with moderate accuracy, acoustic features appear to vary more consistently with symptom severity than with diagnostic group. Speech-based measures may therefore have potential for continuous monitoring of depression, although this possibility requires further longitudinal verification.

Objective Systemic sclerosis (SSc) is an autoimmune disease marked by immune dysregulation, leading to progressive fibrosis and multiorgan dysfunction. Autologous hematopoietic cell transplantation (autoHCT) has demonstrated superiority over conventional immunosuppression in randomized trials yet remains underused in the United States. We report outcomes following implementation of autoHCT as a standard‐of‐care strategy at our institution. Methods We performed a retrospective analysis of consecutive patients with severe SSc undergoing autoHCT between April 1, 2020, and December 31, 2023. Eligibility required progressive disease despite standard immunosuppressive therapy. Primary endpoints were overall survival (OS) and event free survival (EFS). Secondary endpoints included cumulative incidence of relapse and nonrelapse mortality (NRM), organ‐specific outcomes, and transplant‐related complications. Results Twenty‐five patients underwent autoHCT. Median age was 46 years; 80% were female. At a median follow‐up of 23 (interquartile range 16.4–31.9) months, two‐year OS was 91.67% (95% confidence interval [CI] 81.25–100.0) and EFS was 74.51% (95% CI 58.78–94.45). Two‐year cumulative incidence of relapse was 23.93% (95% CI 4.27 –43.59), and NRM was 8.33% (95% CI 2.97–19.64). Significant improvement in Modified Rodnan Skin Score was observed at day +90 and +180 ( P < 0.05), whereas pulmonary function stabilized. Infectious complications occurred in 56% of patients, primarily viral reactivations. Conclusion Implementation of autoHCT for severe SSc in a multidisciplinary care model was associated with favorable survival and meaningful improvement in skin disease, with acceptable toxicity. Earlier referral and optimization of conditioning strategies may further reduce relapse and treatment‐related morbidity.

OBJECTIVE To examine kidney disease outcomes associated with dipeptidyl peptidase 4 inhibitors (DPP-4i). RESEARCH DESIGN AND METHODS In this target trial emulation, claims data from enrollees in commercial, Medicare Advantage, and traditional Medicare health plans were used to identify adults ≥21 years old with type 2 diabetes, with moderate cardiovascular risk, and without stage 3 or worse chronic kidney disease (CKD) initiating alogliptin, linagliptin, saxagliptin, or sitagliptin between 2014 and 2021. The primary outcome was a composite of incident CKD stages 3–5, kidney failure, or kidney replacement therapy. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method and incorporated as inverse probability of treatment weights into proportional hazards models. RESULTS The weighted study cohort included 3,026 individuals starting alogliptin, 38,213 starting linagliptin, 14,934 starting saxagliptin, and 115,091 starting sitagliptin. One year after treatment initiation, the primary outcome occurred in 1.4%, 2.7%, 2.2%, and 2.4% of patients initiating alogliptin, linagliptin, saxagliptin, and sitagliptin, respectively, increasing to 3.2%, 6.2%, 5.0%, and 5.4%, respectively, at 3 years. Alogliptin was associated with lower risk of stage 3 or worse CKD than linagliptin (hazard ratio [HR] 0.50; 95% CI 0.37–0.69), saxagliptin (HR 0.63; 95% CI 0.45–0.86), and sitagliptin (HR 0.58; 95% CI 0.42–0.79), while saxagliptin was associated with lower risk than linagliptin (HR 0.80; 95% CI 0.73–0.87). Conversely, linagliptin was associated with higher risk than sitagliptin (HR 1.15, 95% CI 1.10–1.21). CONCLUSIONS Alogliptin was associated with lower risk of moderate-to-severe kidney disease than other DPP-4i, while linagliptin was associated with higher risk. Limitations include lack of laboratory data and potential unmeasured confounding.

Abstract: Heart valve abnormalities are present in 30% of congenital heart defects. Additionally, there are acquired conditions like rheumatic heart disease. They often require surgery, and in complex cases, valve replacement becomes unavoidable. The current valve replacement options, either mechanical, bioprosthetic, homografts, or autografts, lack key properties for pediatric patient needs: availability, durability, and the ability to grow. Our goal is to review 2 clinically relevant innovations: tissue-engineered heart valves (TEHVs) and partial heart transplantation (PHT). We conducted searches in electronic databases covering the past 25 years using the terms “partial heart transplantation,” “tissue-engineered heart valves,” and their combinations. Decellularized pulmonary homografts outperform cryopreserved homografts and bovine jugular vein conduits in pulmonary valve replacement, showing less stenosis and no infective endocarditis. The European Clinical Study for the Application of Regenerative Heart Valves trial confirmed decellularized pulmonary homograft safety, demonstrating 97.5% freedom from explantation at 5 years. Decellularized aortic homografts showed excellent 97.8% 5-year survival and low endocarditis rates, though increases in transvalvular gradient and regurgitation occurred. Partial heart transplantation uses living valves from donor hearts and accommodates somatic growth. Postoperative immunosuppression in PHT is required but may be limited, as children and valve tissues may possess immune privilege, as evidenced by limited valve injury even in failed orthotopic heart transplants. In a pilot study of 19 infants, with a median follow-up of 26 weeks, increases in annular diameter and leaflet length were observed. Both PHT and TEHVs are promising valve replacement options. While PHT provides a growth-adaptive capability, TEHVs hold the potential for off-the-shelf solutions with minimal immunogenicity.

Abstract Lung fibrosis, including idiopathic pulmonary fibrosis (IPF), represents a spectrum of progressive interstitial lung diseases characterized by disrupted epithelial repair, fibroblast activation, and excess extracellular matrix accumulation. A central feature of fibrotic progression is the loss of alveolar type 2 epithelial (AT2) cell identity and the emergence of aberrant transitional states that fail to support normal regeneration. Based on our re-analysis of multiple publicly available scRNA-seq datasets from the IPF Cell Atlas, S100A2 expression is tightly associated with basal-like reprogramming of AT2 cells and is a top upregulated gene at both mRNA and protein levels in IPF lungs. Furthermore, scRNA-seq data from human lung organoid models reveal that AT2 cells co-cultured with fibroblasts acquire a basal-like phenotype and express high levels of S100A2. Functionally, overexpression of S100A2 in human iPSC-derived lung alveolar epithelial type 2 (iAT2) cells leads to loss of AT2 cellular identity, increased generation of reactive oxygen species, and activation of RAGE signaling pathway. We demonstrate that pharmacologic inhibition of RAGE using Azeliragon preserves AT2 cell populations, associated with reduced oxidative stress in iAT2 cells, and significantly attenuates collagen deposition in bleomycin-induced lung fibrosis models. Collectively, our results indicate that S100A2 is a key driver of epithelial dysfunction in lung fibrosis, promoting loss of AT2 identity, aberrant basal fate acquisition, and persistent epithelial injury. Targeting the unrecognized S100A2–RAGE pathway may offer a new therapeutic strategy to restore epithelial homeostasis in lung fibrosis.

This study investigates how word-initial /l/ and /n/ are phonetically realized in Mandarin Chinese as produced by speakers from three regions: Beijing (close to Standard Mandarin), Changsha (where Xiang, which contains /l/ but not /n/, is also spoken locally), and Meizhou (where Hakka, which contains both /l/ and /n/, is also spoken locally), focusing on acoustic cue use and phonological context effects. Using acoustic analysis and random forest classification, we analyzed five acoustic measures (F2–F1 spacing, F3 frequency, BW1, ΔA1, and A1–P0) and evaluated their contribution to distinguishing the two sounds. Results showed that speakers from different regions used distinct cue weighting strategies: Beijing Mandarin speakers relied more on spectral cues, Meizhou Mandarin speakers showed greater reliance on nasality-related cues, and Changsha Mandarin speakers combined both, with greater variability. Phonological context, including preceding nasals and following vowels, further modulated cue realization in region-specific ways. These findings demonstrate how native phonological background and phonological environment shape the phonetic implementation of a shared Mandarin contrast and illustrate the value of combining acoustic and classification-based approaches for modeling gradient phonetic variation.

Abstract The minichromosome maintenance 2-7 (MCM2-7) proteins form a hexameric protein complex that is the structural core of replicative helicase, which is essential for accurate DNA replication. While their role in replication is well-established, the biological functions of excess chromatin-bound MCM2-7 proteins remain unclear. Here, we identify a transcriptional regulatory function of MCM2-7 through its interaction with nuclear factor κB (NF-κB) p65. We demonstrate that MCM2-7 proteins and NF-κB p65 reciprocally recruit each other to target gene promoters. Consequently, MCM2-7 proteins facilitate the localization of RNA Pol II to NF-κB target gene promoters and along the gene body, thereby promoting transcription of NF-κB target genes. These findings reveal MCM2-7 proteins promote NF-κB target gene transcription by facilitating p65 and RNA Pol II recruitment, offering a potential avenue for fine-tuning NF-κB target gene transcription.