Biomedical research is rapidly adopting artificial intelligence (AI). Yet the inherent complexity of biomedical data preparation requires implementing actionable, robust criteria for ethical and explainable AI (XAI) at the "pre-model" stage, encompassing data acquisition, detailed transformations, and ethical governance. Simple conformance to FAIR (Findable, Accessible, Interoperable, Reusable) Principles is insufficient. Here, we define criteria and practices for reliable AI-readiness of biomedical data, developed by the NIH Bridge to Artificial Intelligence (Bridge2AI) Standards Working Group across seven core dimensions of dataset AI-readiness: FAIRness, Provenance, Characterization, Ethics, Pre-model Explainability, Sustainability, and Computability. Conformance to these criteria provides a basis for pre-model scientific rigor and ethical integrity, mitigating downstream risks of bias and error prior to AI modeling. We apply and evaluate these standards across all four Bridge2AI flagship datasets, spanning functional genomics to clinical medicine, and encode them in machine-actionable metadata bound to the datasets. This framework sets a benchmark for preparing ethical, reusable datasets in biomedical AI and provides standardized methods for reliable pre-model data evaluation.

The past decade has witnessed an unprecedented convergence of exposomic technologies, population-scale genomics, and AI-enabled data science, creating the conditions for a new integrative discipline. Here we introduce ExposoGenomics, defined as the integrative study of how the genome and exposome, treated as jointly dynamic systems, interact across the life course to shape health and disease. ExposoGenomics moves beyond classical gene-environment interaction models by embedding high-dimensional, temporally resolved exposure data within a multi-omic and AI-enabled analytical architecture oriented toward causal discovery, mechanistic understanding, and translational application. We describe the conceptual foundations of this framework, its mechanistic architecture linking external exposures to genomic responses through physiologically based kinetic models and adverse outcome networks, and the analytical approaches, including causal machine learning, graph-based integration, and foundation models, required to realize its potential. We emphasize that computational prediction must be accompanied by rigorous empirical validation, and that findings must be grounded in biologically plausible, causally supported mechanisms. In conjunction with this Perspective, Human Genomics formally launches ExposoGenomics as a dedicated article category and invites submissions that advance this integrative agenda.

We evaluate the converging evidence positioning lithium as a systemic modulator of bone and brain health through shared molecular pathways. This review examines the molecular basis, preclinical data, and clinical observations suggesting that lithium—long established as first-line therapy for bipolar disorder—may simultaneously protect against osteoporosis and neurodegeneration as two clinical conditions increasingly recognized to share biological substrates. Lithium inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes β-catenin, and activates Wnt signaling in neurons and osteoblasts, while also modulating calcium–inositol homeostasis and suppressing NF-κB–mediated inflammation. Large observational studies report lower dementia incidence and reduced fracture risk in long-term lithium users, together with increases in bone mineral density. Declining brain lithium concentrations in patients with Alzheimer’s disease raise the hypothesis that lithium may act as an essential micronutrient rather than solely a pharmacological agent. Bidirectional brain–bone crosstalk involving osteocalcin signaling and sclerostin transport across the blood–brain barrier provides a mechanistic basis for these pleiotropic effects. Lithium offers a unique paradigm for understanding and potentially treating age-related decline in multiple organ systems at subclinical dosage and concentration. However, observational study limitations, optimal dose uncertainties, and toxicity related to long-term usage concerns necessitate rigorous randomized controlled trials before broader clinical recommendations can be made. Future research should focus on optimizing formulation and patient selection to realize lithium’s dual protective potential for bone and brain while minimizing risk.

IntroductionPediatric cardiac surgery with cardiopulmonary bypass (CPB) carries substantial risks of postoperative organ dysfunction and mortality, making the identification of biomarkers for postoperative organ dysfunction crucial for enhancing patient outcomes. As neutrophils play a major role in the perioperative setting and act as double-edge swords to the host, we examined neutrophil transcriptomic profiles in pediatric patients undergoing cardiac surgery with CPB.MethodsWe enrolled into this study from May 31, 2022, to February 22, 2023.Results32% developed postoperative complications, mainly in the respiratory and cardiovascular systems. Patients in the complication group showed higher PELOD-2 scores on postoperative day 2. These patients experienced longer duration of mechanical ventilation and extended ICU and hospital stays. RNA sequencing of neutrophils revealed significant changes in gene expression after CPB, with the myo5c gene emerging as a key downregulated transcript. Its expression was inversely correlated with PELOD-2 score, IL-6 levels, and markers of neutrophil and platelet activation. Furthermore, myo5c-knockout HL60 cells exhibited enhanced neutrophil extracellular traps (NETs) formation upon stimulation, supporting a potential regulatory role for myo5c in neutrophil activation and systemic inflammation.DiscussionWhile myo5c was not an independent predictor of complications, its expression was consistently associated with clinical severity, suggesting it may serve as a useful biomarker for early risk stratification of postoperative complications in this vulnerable pediatric population.

It is increasingly appreciated that the expression of immunoregulatory molecules within tumors have potential to shape a microenvironment that promotes local immunoevasion and immunoregulation. However, little is known about tissue-intrinsic immunomodulatory mechanisms following transplantation. We propose that differences in the phenotype of microvascular endothelial cells impact the alloantigenicity of the graft and its potential to promote immunoregulation following transplantation. We focus this review on the concept that graft-dependent immunoregulation may evolve post-transplantation, and that it is dependent on the phenotype of select subsets of intragraft endothelial cells. We also discuss evidence that long-term graft survival is critically dependent on adaptive interactions among immune cells and endothelial cells within the transplanted tissue microenvironment.

Genetic testing is essential for diagnosing and managing clinical conditions, particularly rare Mendelian diseases. Although efforts to identify rare phenotype-associated variants have focused on protein-truncating variants, interpreting missense variants remains challenging. Deep learning algorithms excel in various biomedical tasks1,2, yet distinguishing pathogenic from benign missense variants remains elusive3–5. Our investigation of AlphaMissense (AM)5, a deep learning tool for predicting the potential functional impact of missense variants and assessing gene essentiality, reveals limitations in identifying pathogenic missense variants over 45 rare diseases, including very early onset inflammatory bowel disease. For the expert-curated pathogenic variants identified in our cohort, AM’s precision was 32.9%, and recall was 57.6%. Notably, AM struggles to evaluate pathogenicity in intrinsically disordered regions (IDRs), resulting in unreliable gene-level essentiality scores for genes containing IDRs. This observation underscores ongoing challenges in clinical genetics, highlighting the need for continued refinement of computational methods in variant pathogenicity prediction.

Rationale: Rare pulmonary diseases (RPDs) in children, such as childhood interstitial lung disease (chILD) and genetic forms of bronchiectasis (including cystic fibrosis [CF] and primary ciliary dyskinesia [PCD]), are difficult to diagnose and often misdiagnosed as asthma, leading to delays in appropriate treatment. Early diagnosis through newborn genetic screening has dramatically increased CF life expectancy, highlighting the importance of early RPD diagnosis for early intervention and preservation of pulmonary function. Anecdotal evidence suggests that RPD are often initially misdiagnosed as severe or difficult-to-treat asthma, and misdiagnosing RPD as asthma delays proper care and exposes children to harmful and costly asthma treatments. However, the extent of this problem in clinical practice has not been explored. Objective: This study aims to estimate the prevalence of undiagnosed RPDs in children with severe asthma, testing the hypothesis that RPDs are more common in severe compared to non-severe asthma cases. Methods: We leveraged data from the Genomic Information Commons (GIC), a network of six academic children's hospitals with access to electronic health records (EHRs), biosamples, and genomic data. Using GIC's PIC-SURE query tool, we analyzed EHRs from 14,907,602 patients for ICD-10 codes related to asthma, severe asthma, bronchiectasis, and chILD. Chi-square tests were used to assess RPD prevalence differences between severe and non-severe asthma patients. For 6,019 asthma patients with exome sequence data, we further analyzed rare genetic variants associated with RPD. Results: Of 441,864 patients diagnosed with asthma across GIC hospitals, 10,753 had severe asthma (2.4%), 11,388 had bronchiectasis (2.6%), and 7,834 had chILD (1.8%). Among patients with severe asthma, RPD prevalence was 5.9 times higher than in those with non-severe asthma (4.7% vs. 0.8%, p < E-16), with notable increases for both bronchiectasis (3.5% vs. 0.5%, 6.8-fold increase) and chILD (1.2% vs. 0.3%, 4.3-fold-increase). Among patients with exome sequence data, those with severe asthma showed a 4.1-fold increase in RPD-related functional genetic variants compared to non-severe asthma cases (17.3% vs. 4.2%, p < 0.00001). Filaggrin (FLG) gene variants, linked to severe asthma, were present in ∼1/3 of severe cases. Excluding FLG variants, enrichment remained significant, especially in genes causing PCD. Conclusion: This large-scale analysis suggests that 1 in every 21 patients with severe asthma carry an RPD diagnosis. Though reliant on ICD-10 codes, our observations are further supported by a 4-fold increase in RPD-causing loss-of-function genetic variants, underscoring the need for heightened clinical awareness of these disorders in patients with severe asthma.

Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were accelerated in global as well as CD4+ T cell-specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.

Despite widely acknowledged sex differences in lipid metabolism and risks for cardiovascular disease, genetic associations contributing to such differences remain incompletely characterized. Here, we performed a sex-stratified genome-wide association study (GWAS) for four lipid profiles to identify loci exhibiting differential effects between males and females. Using whole-genome sequencing data from All of Us Research Program comprising 124,920 participants of diverse ancestry, we conducted GWAS analyses separately in males, females, and a pooled cohort. Our analyses validated previous findings on genes associated with lipid metabolism. In addition, we have found 5 genes showing significant sex-heterogeneous effects, including CELSR2 showing stronger association in males for HDL-C (β female : -0.022, β male : -0.045); GPAM in females for HDL-C (β female : 0.042, β male : 0.013); PLTP in females for LDL-C (β female : 0.06, β male : 0.02); ZPR1 in females for LDL-C (β female : 0.050, β male : 0.014); and CMIP in females for TG (β female : 0.037, β male : 0.019). These findings highlight sex-specific genetic contributions to lipid metabolism and underscore the importance of including sex in evaluating cardiovascular risk.

Artificial intelligence (AI) has transformed pediatric healthcare by supporting diagnostics, personalized treatment strategies, and prognosis predictions. Although it offers significant promise in these areas, its application in pediatric settings poses distinct challenges compared with that in adults due to variable developmental status, the limited availability of pediatric data, and ethical concerns regarding bias and transparency. This narrative review summarizes the key concepts of AI and its clinical applications across clinical fields in the treatment of children and adolescents. Here we highlight the emerging role of large language models in performing administrative tasks and clinical documentation and supporting decision-making. We also address the evolving impact of AI integration in surgical care as an example while exploring ongoing concerns regarding reliability and diagnostic safety. Furthermore, we survey AI-enabled medical devices and discuss the current regulatory frameworks relevant to pediatric care. This review provides a balanced overview of opportunities and challenges from a pediatrician's standpoint and aims to facilitate effective alignment and collaboration with key stakeholders in pediatric healthcare. Pediatricians must implement AI solutions cautiously and accountably to avoid unintended harm and realize their potential.

BACKGROUND:Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development. METHODS:We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling. RESULTS:De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) ∗01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene. CONCLUSIONS:This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition-with HLA-DRB1∗01 as a possible factor-combined with nongenetic risk factors like neuroblastoma.

Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/ exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice- compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.

Background: Sepsis is a leading cause of mortality in hospitalized patients. Autoimmune rheumatic disease (ARD) patients have an elevated risk due to their immune dysfunction, and immunomodulating therapy. Diagnosing sepsis in ARD patients is challenging, as their immune dysfunction can mask symptoms. Delays in diagnosis and treatment contribute to increased mortality risk. This study aims to bridge knowledge gaps, comparing sepsis outcomes in ARD and non-ARD patients. Objectives: To explore sepsis outcomes in individuals with ARD compared to individuals without ARD, using a large database in the United States, the national inpatient sample (NIS) database Methods: The NIS database was queried from 2015 to 2019, with the principal diagnosis of Sepsis and secondary diagnosis was used to identify patients with Autoimmune Rheumatic Diseases combined using pre-verified ICD-10 Codes. Data was appended using latest health care cost and utilization project (HCUP). Univariate analysis with student t test and chi square was performed, and a multivariate regression model was used to generate odds ratio adjusting for hospital level confounders and various co-morbidities. P-value of <0.05 was considered significant, and all the analysis was performed using STATA-MP v 14.2. Results: Among the 10,962,406 reported cases of sepsis in the United States in the NIS database, 417,884 were identified as having ARD. Sepsis patients with ARD demonstrated increased comorbidity burden (56.09% vs. 44.21% with charlson co-morbidity index ≥ 3, p < 0.0001). Various chronic conditions, including hypertension, diabetes, CHF, obesity, CKD, thyroid disease, and liver disease, were more frequent in sepsis patients with ARD all with p < 0.0001. Conclusion: Contrary to prior beliefs, patients with ARDs, despite having more comorbidities, exhibited lower mortality rates, shorter hospital stays, and fewer complications when suffering from sepsis compared to those without ARD. The findings suggest that heightened awareness, regular follow-ups, and distinct immune responses in ARD patients may contribute to these improved outcomes. The study was limited as data used was retrospective, there is no account of disease stage and medications use cannot be tracked. Acknowledgements: NIL. Disclosure of Interests: None declared.Table 1VariableSepsisSepsis with ARDP-valueTotal Number10,544,5224178,84Age (y)64.5 years67.94 yearsMale50.89%31.74%<0.0001Female49.11%68.26%RaceWhite68.64%75.49%<0.0001Black13.83%9.95%Hispanic10.94%9.08%Asian3.1%2.43%Native American0.8%0.95%Others2.7%0.21%Smoking35.19%35.69%=0.0043Charlson comorbidity -index<0.0001018.13%4.36%119.56%18.47%218.09%21.08%344.21%56.09%Income by Zipcode<0.0001$1-$45,00031.27%27.05%$45,000 - $65,00026.18%26.05%$65,000 $- $82,00023.7%25.42%$82000 $ +18.84%21.49%Insurance Type<0.00001Medicare62.29%71.41%Medicaid15.09%9.02%Private18.65%17.84%Self-Pay3.97%1.74%Hospital - region<0.0001North East16.84%16.7%Midwest20.29%23.42%South39.09%35.93%West23.77%23.95%Hospital Bed Sizep=0.8822Small20.92%20.86%Medium30.25%30.35%Large48.83%48.78%HTN63%68.94%<0.0001DM35.7%32.64%<0.0001CHF21.59%24.14%<0.0001Obesity17.87%20.2%<0.0001CKD22.21%22.68%0.6381Alcohol4.78%3.06%<0.0001Liver8.93%8.17%<0.0001COPD20.82%25.33%<0.0001Thyroid14.5%21.75%<0.0001 Table 2OutcomesUnivariate OR(CI)P valueMultivariate OR(CI)P valueMortality0.859(0.83 - 0.88)<0.00010.744 (0.724 - 0.765)<0.0001Length of Stay0.36 (-0.42 - 0.310)<0.0001-0.56 (-0.62 - 0.50)<0.0001Total Hospitalization Charges-$8835.94 (-$9803.3 - -$7868.5)<0.0001-$10916.55 (-$11870.34 - $9962.76)<0.0001Embolic Shock0.684 (0.65 - 0.711)<0.00010.53 (0.511 - 0.552)<0.0001Bleeding0.87 (0.85 - 0.89)<0.00010.81 (0.79 - 0.836)<0.0001Cardiac Arrest0.740 (0.701 - 0.781)<0.00010.722 (0.68 - 0.76)<0.0001Vasopressors1.01 (0.97 - 1.05)0.5290.93 (0.894 - 0.974)0.0002Intubation0.837 (0.820 - 0.85)<0.00010.766 (0.750 - 0.783)<0.0001Pulmonary Embolism0.982 (0.910 - 1.05)0.6490.843 (0.77 - 0.912)0.0001

Pediatric patients with congenital heart diseases (CHD) often undergo surgical repair on cardiopulmonary bypass (CPB). Despite a significant medical and surgical improvement, the mortality of neonates and infants remains high. Damage-associated molecular patterns (DAMPs) are endogenous molecules released from injured/damaged tissues as danger signals. We examined 101 pediatric patients who underwent congenital cardiac surgery on CPB. The mortality rate was 4.0%, and the complication rate was 31.6%. We found that neonates/infants experienced multiple complications most, consistent with the previous knowledge. Neonates and infants in the complication group had received more transfusion intraoperatively than the non-complication arm with lower maximum amplitude (MA) on rewarming CPB thromboelastography (TEG). Despite TEG profiles were comparable at ICU admission between the two groups, the complication arm had higher postoperative chest tube output, requiring more blood transfusion. The complication group showed greater neutrophil extracellular traps (NETs) formation at the end of CPB and postoperatively. Plasma histones and high mobility group box 1 (HMGB1) levels were significantly higher in the complication arm. Both induced NETs in vitro and in vivo . As histones and HMGB1 target Toll-like receptor (TLR)2 and TLR4, their mRNA expression in neutrophils was upregulated in the complication arm. Taken together, NETs play a major role in postoperative complication in pediatric cardiac surgery and would be considered a target for intervention. Key points:Neonates and infants showed highest postoperative complications with more upregulation of inflammatory transcriptomes of neutrophils.Neonates and infants with organ dysfunction had more NETs formation with higher plasma histones and HMGB1 levels.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies.

Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer’s disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.

Background: Septic arthritis is a severe condition with notable morbidity and mortality. Limited knowledge exists regarding factors influencing the readmission of septic arthritis in real-world scenarios. Objectives: To explore 30-day readmission in patients with septic arthritis and identifying independent predictors associated with readmission using National Readmission Database (NRD). Methods: In this retrospective study, the 2019 data from the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project Nationwide Readmission Database were utilized. The primary focus was on determining the rate of readmission for all causes within 30 days post-discharge. Secondary objectives included assessing hospital-level metrics such as length of stay, total hospitalization charges, and costs. The identification of independent risk factors for readmission was carried out through Cox regression analysis. Results: Of the 22,911 total index admissions, 851 resulted in readmissions. Males constituted the majority of index admissions at 64.8%, with a slightly higher readmission rate of 67.09%. The average age for index admissions was 58.1 years, decreasing to 54.1 years in readmitted patients. Insurance distribution showed a decline in readmissions among Medicare-insured patients (from 47.18% to 41.5%) and an increase among Medicaid-insured individuals (from 20.17% to 25.9%). Co-morbidities, such as chronic kidney disease (CKD), Hypertension, and Osteoarthritis, Alcohol Use, Liver Diseases, Thyroid Diseases, HIV, Other Connective Tissue disorders including RA, SLE, Sjogren’s Syndrome were prevalent in both cohorts. On identifying most common diagnosis for Septic Arthritis readmissions, top prevalent were Pyogenic Arthritis (M00.9) and Staphylococcal Arthritis (M00.062). Total Length of Stay for all readmissions in the year 2019 was 6683.75 days with total charges of $57,100,000$ ± $4,881,148. Independent Predictors for Readmissions includes age ([aOR] 0.986, p<0.0001), Medicaid insurance (aOR 1.46, p<0.001), rehab transfer (aOR 3.39, p<0.0001), smoking (aOR 1.46, p<0.0001), and connective tissue combined disorders (aOR 0.73, p<0.05). Conclusion: Septic arthritis imposes a significant strain on hospital outcomes due to recurrent readmissions, leading to substantial healthcare utilization in the year 2019 alone. It is crucial to carefully examine independent predictors of readmissions associated in regards to septic Arthritis. Although it was a limitation that only 2019 data was used, but still smoking was a risk factor for recurrent admissions and readmissions was least in patients who had highest income bracket. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.Table 1Index AdmissionsReadmissionsTotal Number22911851Female35.13%32.90%Male64.8%67.09%Age58.1 years54.1yearInsuranceMedicare47.18%41.5%Medicaid20.17%25.9%Private26.25%25.8%Uninsured6.37%6.25%Charlson co-morbidity index143.65%45.33%226.58%26.27%329.75%28.38%Income in Zip code1 - 47,99931.33%31.87%48,000 - 60,99927.85%26.98%61,000 - 81,99924.66%26.37%82,000+16.1%14.76%Hospital CategoryLarge metropolitan areas with at least 1 million residents50.6%53.61%Small metropolitan areas with less than 1 million residents40.54%38.81%Micropolitan areas7.24%5.78%Others1.59%1.78%Hospital by Teaching StatusMetropolitan non-teaching16.98%14.36%Metropolitan teaching74.17%78.06%Non-metropolitan hospital8.83%7.56%Rehab Transfer0.9%1.02%Smoking44.01%50.96%CHF12.4%10.74%Pleuritis0.9%0.16%Pericarditis4.07%3.40%Osteoarthritis22.30%18.32%Hypertension58.92%57.13%Diabetes Mellitus31.17%32.04%Obesity19.05%17.32%CKD16.96%17.72%Alcohol5.30%4.93%Liver4.50%5.07%Thyroid11.73%8.60%Prednisone2.77%2.83%Sepsis4.32%2.83%Acute Renal Failure2.47%0.54%HIV1.15%1.87%RA5.66%3.79%SLE0.76%1.85%Rheumatoid Arthritis5.6%3.79%Sjogren Syndrome0.71%1.31%Gout11.46%8.51%Connective Tissue combined18.08%13.81%