Citations

Introduction No study to date has examined the association between organism profile and ideal interstage duration in patients undergoing two-stage exchange arthroplasty. The purpose of this study was to evaluate the impact of the type of infecting organism on the optimal timing of reimplantation in this patient population. Methods This retrospective study identified 576 patients with chronic periprosthetic joint infection (PJI) of the knee that underwent two-stage exchange arthroplasty with a minimum 1-year follow-up. PJI was defined using the 2013 Musculoskeletal Infection Society (MSIS) criteria. Patients with a time to reimplantation >180 days from resection arthroplasty (n=76) and those that underwent spacer exchange were excluded (n=49). Treatment failure was defined as any reoperation for infection or PJI-related mortality. Receiver operator characteristic (ROC) curve analyses were used to identify whether the optimal interstage duration differed by infecting organism. Multivariate regression analyses were performed to identify risk factors for failure. Results 451 patients with a mean follow-up time of 5.8 ± 3.6 years were included. Of these, 71 (15.7%) patients experienced failure and 380 (84.3%) experienced success. ROC curve analyses demonstrated that the optimal interstage duration was longest for patients infected with “high-virulence” pathogens (129 days), followed by those with MSSA (117 days), culture negative PJI (98 days), and coagulase-negative Staphylococci (86 days). After controlling for co-variates, regression analyses showed that an interstage duration above the identified cutoff for each pathogen group was a predictor of treatment failure (all p<0.05). Conclusion We found that the ideal interstage duration varied considerably by the type of infecting organism in patients undergoing two-stage exchange. Greater awareness of this data may help guide the optimal timing of reimplantation in this patient population.

Introduction The alpha-defensin test has witnessed a surge in popularity following reports of its superior diagnostic capabilities, when compared to more conventional synovial markers. Despite this, no study to date has evaluated the utility of alpha-defensin for the diagnosis of acute periprosthetic joint infection (PJI). The purpose of this multicenter study was to determine whether the alpha-defensin test provided additional clinical benefit, when compared to synovial white blood cell (WBC) count and polymorphonuclear leukocyte percentage (PMN%), in the diagnosis of acute postoperative PJI. Methods This retrospective study identified all patients who underwent arthrocentesis within 90 days of their primary total joint arthroplasty (TJA) at three institutions. PJI was defined as revision TJA for infection within 2-weeks of joint aspiration with >=1 positive intraoperative culture. Patients were considered aseptic if they had no reoperation for >=1-year after arthrocentesis. Receiver operator characteristic (ROC) curves were used to assess the utility of alpha-defensin, WBC count, and PMN% in the diagnosis of acute PJI. Pairwise comparison was performed to compare whether the area under the curve (AUC) was significantly different between the three markers. Results A total of 143 patients were included. Of these, 85 (59.4%) were infected and 58 (40.6%) were aseptic. After plotting ROC curves, WBC count was found to have the highest diagnostic utility (AUC 0.912, sensitivity 80.0%, specificity 91.2%), followed by PMN% (AUC 0.869, sensitivity 70.5%, specificity 93.0%), and alpha-defensin (AUC 0.812, sensitivity 62.4%, specificity 100%). Using pairwise comparison, the AUC for WBC count was found to be significantly higher than that of alpha-defensin (p=0.005). However, there was no difference in the AUC between alpha defensin and PMN% (p=0.154). Conclusion Based on our findings, it appears that alpha-defensin provides little to no additional clinical benefit in the diagnosis of acute PJI, when compared to synovial WBC count and PMN%.

Introduction The World Health Organization (WHO) endorses male circumcision as an effective human immunodeficiency virus (HIV) prevention intervention in settings where the expected impact is greatest, including Sub-Saharan Africa. Data on cost implications of early infant male circumcision (EIMC) are limited. The ShangRing (SR) is a WHO pre-qualified device for circumcision. We sought to perform a comprehensive cost assessment alongside a randomized controlled trial (RCT) of the SR versus the standard of care Mogen clamp (MoC) for EIMC to enable future scale-up towards a cost-effective HIV prevention strategy. Methods We collected resource utilization and economic data as part of an RCT of infants aged 0–60 days old undergoing EIMC in Kenya, Tanzania, and Uganda. Cost data for both the SR and MoC included baseline facility costs, direct costs, and indirect costs. The Decision Makers Program Planning Tool v1.0 was used to perform a direct cost comparison of these two devices. The Goals model was used to compare the costs of EIMC in 2023 using the present value of money to circumcise an adolescent male 15 years from now. Results A total of 1,378 infant males underwent circumcision, 689 via SR and 689 via MoC. The overall cost of a single EIMC in Kenya, Tanzania, and Uganda were 61.30 United States Dollars ($), $47.14, and $64.59 respectively for the SR, and $56.38, $50.43, and $58.57 respectively for the MoC. In Kenya, EIMC would be less expensive based on nominal present costs in 2023 compared to waiting for adolescent circumcision at age 15 years in 2038. This finding is reversed in Tanzania and Uganda. Conclusions The overall cost of EIMC via SR versus MoC is comparable in an RCT. With scale-up utilizing lower level personnel, the cost of SR may be further reduced. The SR is an attractive alternative for future EIMC initiatives in Sub-Saharan Africa to further reduce HIV burden.

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

Abstract Background and Aims Fibroblast–neutrophil interactions are implicated in ulcerative colitis (UC) treatment resistance, but whether fibroblasts modify neutrophil inflammatory activity remains unclear. We investigated responses to fibroblast exposure, stromal depletion, and α5β1-directed treatment. Methods We integrated human and mouse colonic single-cell RNA sequencing (scRNA-seq), spatial protein profiling (CODEX), fibroblast–neutrophil coculture, and dextran sulfate sodium (DSS) mouse colitis with fibroblast activation protein (FAP) ablation or α5β1-directed treatment. Readouts included cellular representation and protein fluorescence via flow cytometry, neutrophil extracellular trap (NET)-associated elastase activity, RNA programs and epithelial responses using scRNA-seq. Results Inflamed UC tissue contained higher fractions of inflammatory fibroblasts and oncostatin M (OSM)- and CXCR4-associated neutrophils. Inflammatory fibroblasts had higher FAP–α5β1 module scores, and proximity to FAP-high fibroblasts was associated with higher neutrophil OSM and CXCR4 fluorescence. UC fibroblasts increased neutrophil OSM, CXCR4 and myeloperoxidase (MPO) fluorescence and NET-associated elastase activity relative to control fibroblasts, while α5β1-directed treatment attenuated these responses. Both mouse FAP ablation and α5β1 blockade in DSS colitis reduced histologic inflammation and overall neutrophil frequency. Ablation broadly reduced recovered neutrophil representation, whereas blockade increased OSM-positive and PADI4-positive percentages within neutrophils despite lower MPO fluorescence within these subsets. Both interventions were associated with lower epithelial chemokine scores but distinct absorptive and mucus/secretory responses. Conclusions Fibroblast exposure modifies neutrophil inflammatory phenotype and effector-associated activity, identifying candidate therapeutic pathways in UC. Evaluating these responses alongside neutrophil representation and tissue inflammation could inform pharmacodynamic assessment of stromal-directed therapies. Graphical Abstract What You Need to Know Background and Context Fibroblast–neutrophil interactions are associated with treatment resistance in ulcerative colitis. Whether fibroblast exposure modifies neutrophil inflammatory phenotype and effector activity, beyond its established recruitment role, remains unclear. New Findings UC fibroblasts increased neutrophil inflammatory proteins and NET-associated elastase activity; α5β1-directed treatment attenuated these responses. FAP ablation and α5β1-directed treatment reduced colitis and overall neutrophil frequency. α5β1-directed treatment lowered MPO within OSM-positive and PADI4-positive neutrophils despite higher marker-positive percentages. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but distinct barrier-associated and regenerative expression patterns. Limitations Cellular drug targets remain unresolved. Spatial associations and elastase activity do not establish direct contact, NET formation, or clinical efficacy. Clinical Research Relevance Fibroblast-associated pathways offer candidate therapeutic opportunities to modify neutrophil inflammatory phenotype and effector activity in UC. Coculture responses were pharmacologically modifiable, and stromal interventions reduced experimental colitis. Measuring neutrophil frequency, subset proteins, and effector activity alongside tissue inflammation could guide pharmacodynamic assessment. Clinical efficacy and treatment-selection utility require validation. Basic Research Relevance Human coculture provides experimental evidence that fibroblast exposure modifies neutrophil inflammatory proteins and NET-associated elastase activity. FAP+ stromal ablation and α5β1-directed treatment produced distinct patterns of neutrophil representation and subset proteins in colitis. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but differing barrier-associated and regenerative expression patterns. Together, these findings motivate mechanistic studies of how stromal recruitment cues, soluble signals, and matrix-associated interactions regulate neutrophil responses, and whether these changes contribute to reduced epithelial inflammation and tissue repair. Lay Summary Fibroblasts, support cells in the intestine, increased inflammatory activity in immune cells called neutrophils. Blocking a pathway involved in cell attachment reduced these responses in cultures. Targeting fibroblast-associated pathways also reduced experimental colitis, with changes in intestinal lining gene activity related to inflammation, barrier function, and repair. These findings suggest potential approaches to treating ulcerative colitis.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). Cytotoxic combination chemotherapy treatments are the mainstay of PDAC therapy, but patients rapidly develop chemoresistance, highlighting the need to elucidate how chemotherapy alters the TME and whether these changes drive chemoresistance. Here, we examined matched pre- and post-treatment tissue specimens using single-cell RNA-sequencing and found near-universal enrichment after treatment of axonal guidance genes in cancer-associated fibroblasts (CAFs). These neural CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrent lesions had the highest prevalence of neural CAFs versus primary tumors and untreated metastases. Neural CAFs showed elevated non-canonical WNT mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Additionally, in vitro studies revealed enrichment of axonal guidance genes in patient-derived CAF lines upon exposure to chemotherapy or tumor cells. Altogether, these findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising therapeutic target for this disease.