Citations

Liver macrophages are central in maintaining hepatic homeostasis and mediating immune responses during liver injury, including fibrosis. Macrophages may have proinflammatory or antiinflammatory properties, but which properties influence fibrosis remains unclear. To explore the role of macrophages in liver fibrosis, we performed single-cell RNA-seq in a mouse model of liver injury and found that macrophage diversity was increased. Marco was among the most significantly upregulated genes, and a population of Marco hi macrophages increased with injury and spatially segregated to nonfibrotic areas. The macrophage receptor with collagenous structure (MARCO) protein is a scavenger receptor expressed by specific subsets of macrophages, and its role in liver fibrosis is unclear. In vitro induction of Marco in bone marrow–derived macrophages decreased proinflammatory gene expression, increased antiinflammatory and antifibrotic gene expression, and enhanced phagocytosis, indicating a restorative phenotype. Adoptive transfer of MARCO + macrophages in a mouse model of liver fibrosis reduced the expression of extracellular matrix–associated (ECM-associated) genes in hepatic stellate cells (HSCs) and reduced collagen deposition, which did not occur with the transfer of MARCO – macrophages. Therefore, MARCO + macrophages have a tissue restorative role in the liver and attenuate fibrogenesis through interaction with HSCs, thereby providing a potential therapeutic pathway for liver fibrosis.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

This study identifies 3-mercaptopyruvate sulfurtransferase (MPST) as a previously unrecognized regulator of neonatal airway epithelial development. In our neonatal patient-derived three-dimensional organotypic model, hyperoxia reduces MPST, and MPST loss alters mitochondrial metabolism and epithelial differentiation programs. These findings indicate that MPST deficiency contributes to mitochondrial dysfunction under hyperoxic conditions and highlight MPST-linked pathways as potential therapeutic targets to mitigate early-life airway injury and remodeling relevant to infants with bronchopulmonary dysplasia (BPD).

ABSTRACT Objective To (1) validate GAD65‐ELISA detection and quantification for type 1 diabetes mellitus and autoimmune neurological diagnoses, (2) correlate ELISA results (reference range < 5 IU/mL) with established radioimmunoprecipitation assay (RIA; ≤ 0.02 nmol/L), and (3) define ELISA clinical utility and pitfalls. Methods Serum performance for diabetes (FDA‐cleared, undiluted) was verified, and neurological laboratory‐developed serum and CSF dilution protocols were validated to extend the reportable range beyond > 250 IU/mL. ELISA and RIA values were correlated, including established neurological RIA cut‐offs (serum ≥ 20 nmol/L; CSF any positive). Results ELISA met analytical criteria (precision, accuracy, sensitivity, specificity, reference range) in serum and CSF and was clinically equivalent to RIA for autoimmune diabetes. Neurological ELISA cut‐offs were established at 10,000 IU/mL (serum) and 100 IU/mL (CSF). Precision was better below 10,000 IU/mL (CVs < 20%) than above (CVs 30.8% serum; 26.5% CSF). ELISA–RIA correlation and agreement was stronger below the neurological cut‐off (R 2 = 0.89) than above (R 2 = 0.36). Positive agreement for RIA‐defined neurological disease was 100% in serum and CSF; all serums were > 10,000 IU/mL. Clinical specificity was 97.5% in serum and 100% in CSF, exceeding reported RIA specificity. Screen results > 250 IU/mL spanned a wide range of dilution values; many were below the neurological cut‐off. Most patients with paired serum/CSF positivity showed elevated GAD65 IgG indices. Interpretation GAD65 ELISA and RIA have equivalent sensitivity for autoimmune diabetes and neurological testing, with higher specificity for ELISA. A serum cut‐off of 10,000 IU/mL is informative but requires clinical context, and dilution of screen > 250 IU/mL samples is essential for neurological interpretation.

Objective: This study aimed to examine whether parent–child interaction therapy (PCIT), compared with other therapy modalities, was associated with differences in substance use and psychiatric outcomes in a cohort of children with attention-deficit/hyperactivity disorder (ADHD). Methods: This retrospective cohort study was conducted using medical record data from the Rochester Epidemiology Project (REP). The sample included 643 children aged ≤7 years who were diagnosed with ADHD and received either stimulant or nonstimulant medication, along with psychosocial therapy. Participants were categorized into two groups: those who documented exposure to PCIT versus other therapy modalities such as behavioral management, play therapy, cognitive behavioral therapy, parent management training, occupational therapy, speech therapy, parenting class, applied behavior analysis, and social skills training. Conditional logistic regression models were used to examine differences in baseline characteristics and outcomes between the two treatment groups. Results: Individuals in the PCIT group were more likely to have private insurance (66% vs. 57%; p = 0.016) and to fall into higher socioeconomic status quartiles ( p = 0.024) at baseline. PCIT recipients also had a higher prevalence of emotional and behavioral disturbances at baseline (40% vs. 25%; p < 0.001). The median age of the participants at follow-up was 19.6 years, indicating a median follow-up period of approximately 13 years from the initiation of treatment. At follow-up, the PCIT group demonstrated higher rates of problematic alcohol (24% vs. 17%; HR = 1.50, 95% CI: [1.02, 2.20]; p = 0.038) and cannabis use (25% vs. 18%; HR = 1.48, 95% CI: [1.03, 2.15]; p = 0.037). However, after controlling for covariates in the adjusted model, no statistically significant differences emerged between the groups across any substance use outcome. No significant differences were observed in other psychiatric diagnoses or mental health service utilization. Conclusions: Findings indicate that individuals who documented exposure to PCIT demonstrated elevated rates of alcohol and cannabis use in young adulthood, but had no other differences in psychiatric outcomes. While this aligns with prior literature reporting increased substance use risk in ADHD populations, our study cannot confirm this association relative to non-ADHD controls because such a comparison was not included. These associations likely reflect underlying differences in clinical severity and clinical comorbidities at baseline, rather than a direct effect of PCIT. Further investigation is warranted to determine the treatment effects based on baseline risk factors.

High insertion torque can cause conventional bioactive implant coatings to delaminate, generating debris and compromising osseointegration. We developed and evaluated an injectable, self-assembling peptide nanofiber interface designed to be applied in the osteotomy site to enhance biomechanical stability and accelerate bone formation. A multifunctional, injectable gel was formed from self-assembling peptide amphiphiles designed to be osteoinductive, adhesive, and antimicrobial. In a rabbit model, custom titanium implants were placed with either the nanofiber interface or a standard sand-blasted, large-grit, acid-etched (SLA) surface. Osseointegration was evaluated at 3 and 5 wk using micro–computed tomography (micro-CT) for bone-to-implant contact (BIC) and bone volume/total volume (BV/TV), as well as biomechanical reverse torque testing. At 5 wk, implants with the nanofiber interface demonstrated significantly superior osseointegration. BIC reached 58.7% compared to 50.5% for SLA-treated implants ( P < 0.001). BV/TV was also significantly higher at 51.8% versus 42.6% for the SLA group ( P < 0.001). Crucially, biomechanical stability was markedly improved, with the nanofiber group withstanding a reverse torque of 53.2 N·cm, significantly higher than the 41.8 N·cm for the SLA group ( P < 0.01). This injectable nanofiber interface successfully overcomes the limitations of traditional coatings by enhancing bone–implant integration and providing superior biomechanical stability. Uniquely, it is designed to prevent or repair drilling-induced microdamage, occupy peri-implant microcracks with a structural nanoscaffold, and act as a flowable, conformal osteotomy liner when applied prior to implant insertion. This practical approach represents a promising strategy to improve long-term clinical outcomes, particularly in patients with compromised bone quality or a higher risk of implant failure.

Introduction: Upper limb spasticity can result from a variety of insults to the central nervous system. Disruption of the closely regulated spinal reflex arc, owing to loss of brain inhibition, results in an imbalance between antagonist and agonist muscle groups, leading to a loss of fluid coordination of motion across joints. Management strategies: A detailed, individualized assessment of each patient is mandatory in a multidisciplinary setting. Although there are objective parameters which guide treatment, variation and customization of strategies are needed for each patient, including defining a functional vs. a non-functional hand, and whether mobility or stability is the primary goal for surgery. Challenging areas in spasticity management: Surgical options include bony, tendon and nerve procedures. These aim to reduce tone, release contractures or reanimate paralysed muscles. This article examines four challenging areas in decision making for choosing these options: lengthening vs. hyperselective neurectomy for tone management, stability vs. mobility in wrist spasticity, grasp and release recovery through finger flexion and extension, and dystonia. Evidence-based treatments are discussed where available, along with key unresolved issues and future research directions. Conclusion: Restoring balance in the spastic upper limb, especially when voluntary control is lost, remains one of the most complex challenges in hand surgery. A thorough understanding of biomechanical principles and neurological pathways is necessary for the hand surgeon. Furthermore, working within a multidisciplinary team is essential to utilize a comprehensive array of assessment tools, ensuring accurate diagnosis and individualized patient care.

ABSTRACT Electrocardiography (ECG) is a critical diagnostic tool for identifying cardiac conditions. While standard lead positions are widely used to ensure diagnostic accuracy, alternative lead placements have been developed to address specific clinical scenarios. These alternative configurations can overcome physical or technical challenges, enhance rhythm assessment, improve signal quality, and provide greater specificity for certain conditions, ultimately enabling more personalized diagnostic strategies. This paper examines the clinical significance of alternative ECG lead positions, highlighting their advantages, limitations, and potential applications in various clinical settings.