Citations

ABSTRACT Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis that commonly presents with multiorgan involvement of the upper airways, lungs, and kidneys. We report a 55 year-old-man who presented with painful oral ulcers, diffuse joint pain, epistaxis, and intermittent maroon bowel movements. Infectious evaluation was unremarkable. Rheumatologic evaluation demonstrated elevated c-anti-neutrophil cytoplasmic antibody and proteinase 3 antibodies. Colonoscopy with terminal ileum biopsies demonstrated angiocentric inflammatory findings supportive of a diagnosis of GPA. This case was unusual in its presentation with predominately oral manifestations. A diagnosis of GPA should remain on the differential for patients with gastrointestinal bleeding, and these systemic symptoms require a high level of suspicion to lead to timely diagnosis.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

Biomaterials like gold nanorod-embedded gelatin methacrylate (GelMA-GNR) hydrogels support the delivery of regenerative cells such as human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), enhancing EHT performance.

Background: Autonomic dysfunction is common after spinal cord injury (SCI). There are currently limited tools to comprehensively characterize its deficits. While individual established autonomic tests have a long history and sound scientific background, translating these autonomic testing results to inform clinical understanding is a major barrier. Objectives: To assess a strategic battery of autonomic tests to characterize and act as a biomarker of autonomic regulation for individuals with SCI and to develop a novel graphical representation of these data to facilitate understanding of autonomic dysfunction after SCI. Methods: We outline a battery of six laboratory autonomic tests that were curated to collectively describe the ability of individuals with SCI to inhibit and recruit sympathetic activity through the injured spinal cord. Heart rate/blood pressure variability, bolus phenylephrine, hand and foot cold pressor, Valsalva maneuver, and bladder pressor are herein described. Incorporating normative control data for 30 uninjured individuals completing this testing battery, we further demonstrate the utility of a composite biomarker, comparing these control results to 11 individuals with SCI. Results: Results demonstrate strong normality of data with testing psychometrics, suggesting stable reproducibility with repeat testing. Even in this preliminary sample of individuals with SCI, clear differences begin to emerge compared to uninjured norms. This illustrates the ability of this collective testing battery to characterize autonomic regulation after SCI. To aid in clinical translation, we further present a graphical representation, an autonomic phenotype , which serves as a snapshot of how normal or abnormal sympathetic inhibition and recruitment of activation may be after SCI. Conclusion: Utilizing these autonomic phenotypes, three example cases of individuals with SCI highlight evidence of varied degrees of autonomically complete SCI. Together, this represents a key advancement in our understanding of autonomic function after SCI.

Background Statin Choice is a shared decision-making encounter tool embedded in the electronic health record. Objective To describe the association between the use of Statin Choice, statin prescriptions by clinicians, prescription fills (primary adherence), and statin adherence at 12 mo (secondary adherence). Design Observational cohort study at the Cleveland Clinic Health System. Subjects Statin-naïve adults aged 40 to 75 y with a 10-y atherosclerotic cardiovascular disease (ASCVD) risk of ≥5% and a primary care appointment between January 2020 and July 2021. Main Measures The primary exposure was the use of Statin Choice during a clinical encounter. We measured whether the use of Statin Choice was associated with statin prescriptions. We measured statin adherence based on pharmacy fill data at 60 d (primary adherence) and 12 mo (secondary adherence). We used mixed-effects logistic regression to estimate the adjusted odds of statin prescriptions and adherence at the 3 time points by the use of Statin Choice. Key Results Among 17,001 statin-naïve patients, 13% viewed Statin Choice and 7% were prescribed a statin. The median ASCVD risk was 10%. Patients who were shown Statin Choice had 9.04 higher odds of being prescribed a statin compared with patients not shown Statin Choice (95% confidence interval [CI]: 7.86–10.4). Among patients prescribed a statin, the use of Statin Choice was associated with 5.75 higher odds of primary adherence compared with usual care (95% CI: 4.22–7.83). At 12 mo, Statin Choice use was significantly associated with adherence in the unadjusted analysis (OR: 1.58; 95% CI: 1.05–2.08) but was not significant after adjustment for patient factors. Patients shown Statin Choice had an average of 12 mg/dL reduction in low-density lipoprotein cholesterol at 12 mo (95% CI: −16 mg/dL, −10) compared with those not shown Statin Choice. Conclusion In this observational study, Statin Choice use was strongly associated with statin prescription and fills and weakly associated with adherence to statins for up to 1 y. A randomized trial is needed to confirm causality. Highlights Statin Choice is an electronic health record–embedded shared decision-making encounter tool available for free in many health care systems. Small randomized controlled trials have found modest associations between the use of Statin Choice and statin adherence using patient-reported data. In our large study using pharmacy fill data, clinician use of Statin Choice during a medical encounter was associated with significantly greater patient adherence with statins up to 1 y later. Exposure to Statin Choice was associated with a significant reduction in low-density lipoprotein cholesterol over 1 y.

ABSTRACTImmunotherapy of autoimmune diseases has expanded substantially, yet autoimmunity remains incurable, and patients suffer from chronic destructive tissue inflammation that fails to resolve. Mechanisms underlying the endurance of autoimmune memory and the lack of exhaustion are beginning to be understood. Here, we review emerging data on how decentralization of cellular immunity contributes to persistent autoimmune responses and chronicity of autoimmune tissue inflammation. Two processes are recognized as ensuring lasting immune memory: the generation of tissue‐resident memory T cells (TRM) and the formation of tertiary lymphoid structures (TLS). TLS, lymphoid aggregates formed outside of lymphoid organs, develop under conditions of chronic immune stimulation, such as autoimmune disease, anti‐tumor immunity, and during immune aging. TLS display heterogeneity in structure and cellular composition that may determine whether they ultimately serve as protective or pathogenic elements. Recent data have implicated TLS as a critical resource in upholding autoimmune responses, emphasizing their role in harming the host. In patients with autoimmune vasculitis, adventitial TLS drives protracted autoimmune disease by housing TCF1hi CD4+ T stem cells that escape exhaustion and provide a continuous supply of pathogenic effector T cells to the disease lesions. The local production and stemness of CD4+ T cells bring resilience to autoreactive immunity, defining novel therapeutic targets in the management of autoimmune disease.

Preterm premature rupture of membranes (pPROM) is a leading cause of preterm birth (PTB) and is increasingly recognized for its association with neurodevelopmental disorders (NDDs). The disruption of fetal membrane integrity introduces potential infection and inflammation into the intrauterine environment, triggering immune responses that may affect fetal development. Placental inflammation plays a pivotal role in mediating these effects, exposing the fetus to cytokines, oxidative stress, and potential microbial insults that contribute to adverse neurodevelopmental outcomes. This review examines the current evidence of the mechanistic pathways linking pPROM-induced placental inflammation to NDDs, emphasizing the roles of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in the inflammatory responses. We discuss how these immune activations lead to immune cell recruitment and excessive (or uncontrolled) production of inflammatory mediators, leading to an overall inflammatory imbalance that has been linked to disrupted fetal brain development in animal models. Animal models provide critical insights into how both sterile and pathogenic placental inflammation alter fetal neurodevelopment, while human studies, though limited, highlight promising biomarkers and potential therapeutic targets. This review identifies critical knowledge gaps and outlines future directions to mitigate the impact of placental inflammation on long-term infant health.

Chronic pain affects a significant portion of the population, with fewer than 30% achieving adequate relief from existing treatments. This study describes the humanization methodology and characterization of an effective non-opioid single-chain fragment variable (scFv) biologic that reverses pain-related behaviors, in this case by targeting P2X4. After nerve injury, ATP release activates/upregulates P2X4 receptors (P2X4R) sequestered in late endosomes, triggering a cascade of chronic pain-related events. Nine humanized scFv (hscFv) variants targeting a specific extracellular 13-amino-acid peptide fragment of human P2X4R were generated via CDR grafting. ELISA analysis revealed nanomolar binding affinities, with most humanized molecules exhibiting comparable or superior affinity compared to the original murine antibody. Octet measurements confirmed that the lead, HC3-LC3, exhibited nanomolar binding kinetics (KD = 2.5 × 10−9 M). In vivo functional validation with P2X4R hscFv reversed nerve injury-induced chronic pain-related behaviors with a single dose (0.4 mg/kg, intraperitoneal) within two weeks. The return to naïve baseline remained durably reduced > 100 days. In independent confirmation, the spared nerve injury (SNI) model was similarly reduced. This constitutes an original method whereby durable reversals of chronic nerve injury pain, anxiety and depression measures are accomplished.

Background and Aims: Reducing avoidable readmissions in cirrhosis is challenging. Enhanced engagement using health information technology (HIT) interventions and caregivers lowered readmissions in an open-label study of the Patient Buddy App (PBA). Aim : Multicenter trial of PBA versus standard of care (SOC) to reduce avoidable readmissions. Approach and Results: An open-label, randomized clinical trial was performed at 3 sites to study the effect of PBA (HIT) versus SOC in cirrhosis inpatients with adult caregivers (dyads). Initial randomization was 1:1:1 between SOC, HIT only, and HIT+ visits. However, due to COVID-19, an unplanned study redesign required a combined HIT versus SOC. Primary outcome : Avoidable readmissions (decided by a blinded monitoring board). Secondary outcomes were all-cause readmission and stakeholder input. PBA focused on medication adherence, cognitive testing, and symptoms, and was remotely monitored by study staff. In all, 464 subjects (232 dyads) were enrolled [Virginia Commonwealth University (VCU): 120, Mayo: 40, Department of Veterans Affairs (VA): 72; 116 dyads/group]. Avoidable readmissions were significantly higher in SOC versus HIT (19.8% vs. 10.3%, p =0.04) with OR of 2.14 (95% CI 1.01–4.54) and remained significant even after removing pre-COVID HIT+ visits patients (19.8% vs. 9.3%, p =0.040) with OR of 2.41 (95% CI 1.02–5.69). All-cause readmissions were higher in SOC versus HIT (48% vs. 30%, p =0.005). App evaluation/engagemen t : 1660 alerts were sent; mostly related to HE. Most dyads were satisfied with the app. Conclusions: In a multicenter randomized clinical trial of 464 cirrhosis inpatients and their CGs across several practice settings, the PBA was associated with lower avoidable readmissions at 30 days post-discharge compared to SOC.