Feinstein Institute for Medical Research

Vagus nerve stimulation (VNS) is emerging as potential treatment for several chronic diseases. However, limited control of fiber activation, e.g., to promote desired effects over side effects, restricts clinical translation. Towards that goal, we describe a VNS method consisting of intermittent, interferential sinusoidal current stimulation (i²CS) through multi-contact epineural cuffs. In experiments in anesthetized swine, i²CS elicits nerve potentials and organ responses, from lungs and laryngeal muscles, that are distinct from equivalent non-interferential sinusoidal stimulation. Resection and micro-CT imaging of a previously stimulated nerve, to resolve anatomical trajectories of nerve fascicles, demonstrate that i²CS responses are explained by activation of organ-specific fascicles rather than the entire nerve. Physiological responses in swine and activity of single fibers in anatomically realistic, physiologically validated biophysical vagus nerve models indicate that i²CS reduces fiber activation at the interference focus. Experimental and modeling results demonstrate that current steering and beat and repetition frequencies predictably shape the spatiotemporal pattern of fiber activation, allowing tunable and precise control of nerve and organ responses. When compared to equivalent sinusoidal stimulation in the same animals, i²CS produces reduced levels of a side-effect by larger laryngeal fibers, while attaining similar levels of a desired effect by smaller bronchopulmonary fibers.

Objective The presence of anti‐nuclear antibodies (ANAs) is characteristic for systemic lupus erythematosus (SLE). Antibody dynamics over time are thought to reflect the cellular source of ANAs and their therapeutic targetability. Anti‐dsDNA is the most prevalent and well‐studied of all ANAs, and fluctuations in anti‐dsDNA serum levels are associated with disease activity. Antibody dynamics of other ANAs, such as antibodies targeting RNA‐binding proteins (RBPs), are often considered more stable compared to anti‐dsDNA. However, anti‐RBPs may be heterogeneous in nature and their fluctuation has not been extensively analysed. Therefore, we aimed to study the dynamics of the different ANAs and their susceptibility to B cell targeting treatments in SLE patients. Methods Seroconversion of specific ANAs was analyzed using electronic health records from SLE patients. Titers of specific ANAs and anti‐varicella zoster virus (VZV) were determined in serum from a longitudinal SLE patient cohort, and serum from SLE patients treated with rituximab and belimumab. Results Anti‐Sm/RNP, like anti‐dsDNA titers, seroconverted more frequently compared to anti‐SS‐A/SS‐B. Furthermore, anti‐Sm/RNP as well as anti‐dsDNA titers, but not anti‐SS‐A/SS‐B titers, fluctuated significantly compared to stable anti‐VZV controls. Likewise, reductions in anti‐dsDNA and anti‐Sm/RNP titers after B cell depleting treatment were comparable in magnitude. However, only anti‐dsDNA titer reductions associated with clinical outcomes. Conclusions Together, these results show that anti‐Sm/RNP and anti‐dsDNA, in contrast to anti‐SS‐A/SS‐B, frequently fluctuate and their levels can decrease following B cell‐targeted treatments. Thus, distinct ANAs have variable kinetics, potentially reflecting their derivation from different B cell differentiation pathways. image

Objective The objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis. Methods The Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus‐based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3–5 years for those achieving complete renal response. Conclusion This guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.

Objective The objective is to provide evidence‐based and expert guidance for the screening, treatment, and management of lupus nephritis. Methods The Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus‐based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3–5 years for those achieving complete renal response. Conclusion This guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.

Objectives To achieve consensus on domains of active disease for inclusion in a novel outcome measure for SLE randomised controlled trials (RCTs), the Treatment Response Measure for SLE (TRM-SLE). Methods Domains nominated by TRM-SLE Taskforce members were rated in a two-stage modified Delphi study. Each stage comprised two online survey rounds separated by a structured discussion meeting. In Stage 1, expert lupus clinicians and patient representatives rated domain ‘importance’ (impact on symptoms, function or survival). In Stage 2, clinicians rated ‘important’ domains on three characteristics relevant to RCT utility: ‘appropriateness’ for evaluating change in disease activity, ‘representation’ in patients with active SLE and ‘measurability’ in an RCT context. Consensus for domain inclusion was prespecified as all four characteristics achieving a rating ≥7 on a 1–9 scale by ≥70% of participants. Results Domain nominations from 36/59 (61%) TRM-SLE Taskforce members yielded 34 potential domains which were rated in the modified Delphi study. At least one Delphi round was completed by 87 clinicians and 13 patient representatives. In Stage 1, 14 domains met consensus on ‘importance’ in both clinician and patient groups, and 11 domains met consensus among patients only. After Stage 2, eight of these domains also reached consensus on ‘appropriateness’, ‘representation’ and ‘measurability’: alopecia, arthritis, haemolytic anaemia, nephritis, mucosal ulcers, rash, serositis and thrombocytopenia. Conclusions Considering patient and clinician perspectives, we reached consensus to include eight disease activity domains for future development into the novel TRM-SLE clinical trial outcome measure, aiming to improve trial interpretability and success.

Background Many studies have highlighted the detrimental effect of childhood maltreatment (CM) on depression severity and the course of illness in major depressive disorder (MDD). Yet our understanding of how CM influences the dynamic symptom change throughout a patient’s trajectory remains limited. Hence, we investigated the impact of CM on depression severity in MDD with a focus on various treatment phases during inpatient treatment and after discharge (1 or 2 years later) and validated findings in a real-world setting. Methods We used longitudinal data from a cohort study sample ( n = 567) and a clinical routine sample ( n = 438). CM was measured with the Childhood Trauma Questionnaire (CTQ), and depression severity was assessed using Beck’s Depression Inventory (BDI). The long-term clinical trajectory was assessed using the Life Chart Interview. Results Our analyses revealed that CM significantly increased depression severity before, during, and after inpatient therapy in both samples. Although CM was associated with higher depression severity at the beginning of inpatient treatment and lower remission rates upon discharge, no discernible impact of CM was evident on the relative change in symptoms over time during inpatient treatment. CM consistently predicted higher relapse rates and lower rates of full remission after discharge during long-term follow-up in both samples. Conclusions Our findings affirm the link between CM and the development of more severe and persistent clinical trajectories within real-world clinical settings. Furthermore, conventional psychiatric treatments may not lead to comparable outcomes for individuals with a history of CM, underscoring the necessity for tailored therapeutic interventions.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.

Introduction Hepatic ischemia-reperfusion (I/R) can cause further liver injury through a cascade of complex cellular events. Damage-associated molecular patterns (DAMPs) released from stressed or damaged cells in the liver contribute to this pathology, leading to hyperinflammation, organ tissue damage, and high mortality. We have developed a novel compound, Opsonin Peptide 18 (OP18), which exhibits strong binding affinity for multiple DAMPs, including extracellular cold-inducible RNA-binding protein (eCIRP), high-mobility group box 1 (HMGB1), and histone H3, thereby enhancing the clearance of those DAMPs by phagocytic cells. In this study, we hypothesized that OP18 mitigates hepatic I/R injury by suppressing DAMPs-induced inflammation. Methods Adult C57BL/6 mice were subjected to 70% hepatic ischemia for 60 min immediately followed by intraperitoneal ( i.p. ) administration of either formic acid in PBS (vehicle) or 0.2 mg/kg body weight (BW) OP18 (treatment). After 24 h, blood and liver tissues were collected for the measurement of systemic inflammatory markers, including cytokines, liver enzymes, chemokines, and myeloperoxidase (MPO) activity. Liver tissue damage and cell death were evaluated histologically. The survival rate was monitored for 10 days post hepatic I/R. Results In the hepatic I/R mouse model, OP18 treatment significantly decreased the elevated plasma levels of IL-6, TNFα, IL-1β, AST, ALT, and LDH compared to vehicle group. Moreover, OP18 markedly decreased liver tissue mRNA levels of IL-6, TNFα, IL-1β, macrophage inflammatory protein-2 (MIP-2), and keratinocyte chemoattractant (KC), as well as MPO activity. Histological analysis revealed that OP18 treatment significantly attenuated liver tissue damage and cell death in hepatic I/R mice. Furthermore, the administration of OP18 significantly improved the survival after hepatic I/R injury. Conclusion OP18 mitigates inflammation and tissue damage following hepatic I/R injury and improves survival. Thus, OP18 has potential as a promising therapeutic strategy for hepatic I/R injury.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P < .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177

The nervous system coordinates with the immune system to detect and respond to harmful stimuli. Inflammation is a universal response to injury and infection that involves the release of cytokines. While it is known that information about cytokines is transmitted from the body to the brain, how the nervous system encodes specific cytokines in the form of neural activity is not well understood. Using in vivo calcium imaging, we show that vagal sensory neurons within the nodose ganglia exhibit distinct real-time neuronal responses to inflammatory cytokines. Some neurons respond selectively to individual cytokines, while others encode multiple cytokines with distinct activity patterns. In male mice with induced colitis, inflammation increased the baseline activity of these neurons but decreased responsiveness to specific cytokines, reflecting altered neural excitability. Transcriptomic analysis of vagal ganglia from colitis mice revealed downregulation of cytokine signaling pathways, while neuronal activity pathways were upregulated. Thus, nodose ganglia neurons perform real-time encoding of cytokines at the first neural station in a body-brain axis, providing a new framework for studying the dynamic nature of neuroimmune communication.

Purpose of review Adenosine signaling is emerging as a key regulator of hematopoietic lineage commitment, influencing both erythropoiesis and myelopoiesis. This review explores the distinct roles of adenosine receptors in balancing these processes, particularly under stress conditions. Since adenosine extracellular levels are increased in multiple hematological disorders, including sickle cell disease, deciphering the mechanisms downstream of adenosine receptor activation is crucial to understand the pathophysiology of these conditions. Recent findings Extracellular adenosine levels in the bone marrow microenvironment are tightly regulated by CD39/CD73 activity and ENT1 uptake. Recent studies have shown that ENT1-mediated adenosine transport is crucial for adenosine intracellular metabolism and normal erythropoiesis, while increased extracellular adenosine levels impact hematopoietic differentiation through adenosine receptor activation. . High dose of exogenous adenosine inhibits erythroid proliferation by inducing G1 arrest and p53-mediated apoptosis. Furthermore, A 2B and A 3 receptor signaling inhibits erythroid differentiation, while adenosine signaling through A 3 also favors granulopoiesis. Summary Collectively, these findings highlight adenosine signaling as a critical and multifaceted regulator of hematopoietic balance, offering novel insights into its therapeutic potential for managing disorders characterized by ineffective erythropoiesis and aberrant myelopoiesis.

Background Class A CpG-oligonucleotides (ODNs), a Toll-like receptor 9 (TLR9) agonist, have been applied for treating inflammatory diseases and cancer in preclinical studies and clinical trials. A recent study has reported that class A ODNs can activate the Cyclic GMP-AMP synthase (cGAS) signaling to regulate the inflammatory response in human monocytes. However, it remains unknown whether class A ODNs can activate the cGAS pathways in other cell types, such as fibroblastic reticular cells (FRC), which play critical roles in modulating the immune environments during inflammatory diseases and cancer. Methods To understand the role of class A ODN in regulating the cGAS signaling in FRC, we treated mouse FRC and human fibroblast with class A ODN, a cGAS agonist (HT-DNA), and combined class A and HT-DNA. Results Unexpectedly, we found that class A ODNs suppress the cGAS level and downstream signaling in human and murine FRC. The class A ODN-induced suppression effect on cGAS is limited in FRC, but not other immune cell types, and is independent of TLR9. Performing pulldown assay and Mass spectrum, we found that class A ODNs regulate the cGAS level post translationally by interacting with cGAS and ZNF598, an E3 ubiquitin ligase. Conclusion Our data reveal an unrecognized off-target effect of class A ODN on suppressing the cGAS signaling in FRCs, which should be considered when designing class A ODN regimens for inflammatory diseases and cancer.

Schizophrenia is associated with structural and functional changes in the central nervous system, including the most distal part of it, the retina. However, the question of whether retinal atrophy is present before individuals develop schizophrenia or is a secondary consequence of the disorder remains unanswered. Here we address this question by examining the association between polygenic risk scores for schizophrenia and retinal morphologies in individuals without a schizophrenia diagnosis. We used population data for 34,939 white British and Irish individuals from the UK Biobank. Our robust regression results show that higher polygenic risk scores for schizophrenia were associated with thinner overall maculae, while controlling for confounding factors ( b = −0.17, P = 0.018). Similarly, we found that greater polygenic risk scores for schizophrenia specific to neuroinflammation gene sets were associated with thinner ganglion cell inner plexiform layers ( b = −0.10, self-contained P = 0.014, competitive P = 0.02). These results provide new evidence for genetic factors that could predispose individuals to heightened neuroinflammatory responses. Over time, these responses could contribute to neurodegenerative processes such as retinal thinning.

Background Tardive dyskinesia (TD) is a severe and persistent involuntary movement disorder associated with long-term antipsychotic treatment. TD is likely underreported and misdiagnosed in routine practice, and there is a need to understand the proportion of patients who may experience TD but receive no formal diagnosis. This information could support the characterisation of patient populations that may benefit from novel therapeutic interventions. This study aimed to identify and describe patients with diagnosed or undiagnosed TD. Demographic and clinical features associated with an ICD-9/10 diagnosis of TD were explored. Methods A retrospective study was conducted using de-identified electronic health record (EHR) data captured between 1999 and 2021 in the US. A cohort of 32,558 adults with schizophrenia-spectrum disorders, major depressive disorder with psychosis or bipolar disorder with psychosis who were prescribed antipsychotics was selected. Abnormal movements associated with TD and presence of TD documented in semi-structured EHR data were extracted through manual review of text recorded as part of the mental state examination. Patients with a recorded diagnosis of TD were identified based on the presence ICD-9/10 codes within structured portions of medical records: ICD-9: 333.85; ICD-10: G24.01. Logistic regression was used to assess the association between patient characteristics and an ICD diagnosis. Results Altogether, 1,301 (4.0%) patients had either description of abnormal movements associated with TD (n=691) or documented TD (n=610) within semi-structured EHR data. Of those patients, only 64 (4.9%) had an ICD-TD diagnosis in structured EHR data. When the cohort was limited to those with documented TD in semi-structured EHR data, 56 (9.2%) had an ICD-TD diagnosis. Black/African-American race was associated with lower odds of ICD diagnosis compared with white race (OR=0.46, 95%CI=0.20–0.95, p=0.04). Treatment in community mental health centres was associated with increased odds of an ICD diagnosis compared to an academic medical centre (OR=adjusted OR=2.02, 95%CI=1.09–3.74, p=0.03). Conclusions This study highlights a pressing need for clinicians to better recognise and diagnose TD, which in turn may contribute to increased access to treatments for patients. A recorded ICD diagnosis of TD may be driven by factors related to both the patient and clinical setting.

Parkinson’s disease is a progressive neurodegenerative condition with a considerable health and economic burden¹. It is characterized by the loss of midbrain dopaminergic neurons and a diminished response to symptomatic medical or surgical therapy as the disease progresses². Cell therapy aims to replenish lost dopaminergic neurons and their striatal projections by intrastriatal grafting. Here, we report the results of an open-label phase I clinical trial (NCT04802733) of an investigational cryopreserved, off-the-shelf dopaminergic neuron progenitor cell product (bemdaneprocel) derived from human embryonic stem (hES) cells and grafted bilaterally into the putamen of patients with Parkinson’s disease. Twelve patients were enrolled sequentially in two cohorts—a low-dose (0.9 million cells, n = 5) and a high-dose (2.7 million cells, n = 7) cohort—and all of the participants received one year of immunosuppression. The trial achieved its primary objectives of safety and tolerability one year after transplantation, with no adverse events related to the cell product. At 18 months after grafting, putaminal ¹⁸Fluoro-DOPA positron emission tomography uptake increased, indicating graft survival. Secondary and exploratory clinical outcomes showed improvement or stability, including improvement in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III OFF scores by an average of 23 points in the high-dose cohort. There were no graft-induced dyskinesias. These data demonstrate safety and support future definitive clinical studies.