Publications

The substantial adverse effects associated with opioid-based analgesia and its contribution to postoperative dependence have prompted a shift toward multimodal, opioid-sparing perioperative strategies. Non-opioid analgesics now form the cornerstone of contemporary perioperative management and Enhanced Recovery After Surgery (ERAS) pathways. This review synthesizes current evidence on the efficacy, safety, and clinical utility of major non-opioid analgesic classes, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, N-methyl-D-aspartate (NMDA) antagonists, intravenous lidocaine, gabapentinoids, α2-agonists, regional anesthesia techniques, and glucocorticoids, for postoperative pain management. Evidence from randomized controlled trials, systematic reviews, and meta-analyses was evaluated with emphasis on analgesic effectiveness, opioid-sparing capacity, recovery outcomes, and adverse effects. The efficacy of non-opioid multimodal analgesia (MMA) stems from the synergistic targeting of distinct pain pathways. Across drug classes, non-opioid agents demonstrate clinically meaningful opioid-sparing effects while providing analgesia that is comparable to opioid-based regimens. Acetaminophen and NSAIDs are cornerstones of MMA, supported by extensive high-quality evidence. NMDA antagonists such as ketamine show particular benefit in major surgical procedures for modulating central sensitization and preventing chronic pain, whereas intravenous lidocaine has unique advantages in accelerating gastrointestinal recovery and may reduce hospital length of stay. Gabapentinoids may serve as adjuncts but exhibit heterogeneous efficacy and a side-effect profile (e.g., sedation) that necessitates selective use. Preoperative α2-agonists consistently prolong analgesia and reduce perioperative opioid requirements. As a core component of MMA, regional anesthesia techniques demonstrate robust reductions in both prolonged postoperative opioid use and the incidence of chronic postsurgical pain, and perioperative glucocorticoids such as dexamethasone contribute potent dual analgesic and antiemetic effects. The collective evidence indicates that MMA, integrating agents with complementary mechanisms, provides superior pain control, enhanced functional recovery, and meaningful reductions in opioid exposure. Broader implementation of standardized, procedure-specific multimodal protocols may further decrease opioid-related harms and strengthen alignment with ERAS principles. Future research should prioritize long-term outcomes and optimization of multimodal combinations to advance the transition toward a post-opioid paradigm in surgical care.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease mainly driven by aquaporin-4 antibodies (AQP4-IgG). During an attack, AQP4-IgG activates the complement system, leading to astrocyte destruction, inflammation, neuronal damage, and thus devastating and often irreversible neurologic deficits. Terminal complement inhibitors such as eculizumab and ravulizumab effectively prevent relapses, yet their therapeutic potential in stopping ongoing complement-mediated injury during acute attacks remains insufficiently explored.

METHODS: We conducted a multinational retrospective case series across NMOSD-specialized centers in 6 countries, analyzing 33 AQP4-IgG-positive patients (mean age: 48.1 years; 28 women) treated with component 5 (C5) inhibition during or shortly after acute relapse (mean 20.1 days from symptom onset; range 2-62). Eculizumab was used in 25 patients and ravulizumab in 8. Two additional patients were excluded because of delayed treatment initiation beyond 62 days.

RESULTS: Lesion locations included myelitis (57.6%) and optic neuritis (30.3%). Expanded Disability Status Scale scores worsened from a pre-relapse median of 0 (interquartile range [IQR] 0-2) to a nadir of 6.5 (IQR 3.5-8), improving to 3.5 (IQR 3-6.5) at 1-3 months and 2.5 (IQR 2-6) at 6 months. All patients stabilized clinically; 20 continued C5 inhibition as attack-preventing therapy. Good, moderate, and poor/absent recovery were observed in 15, 11, and 7 patients, respectively. Earlier treatment was associated with better outcomes: treatment within 21 days yielded an odds ratio of 1.58 (95% CI 0.32-8.52) for good response. Plasma exchange was administered in 57.6% and was associated with higher overall response rates, but not with good response alone.

DISCUSSION: These findings highlight the potential of complement inhibition as a treatment option for acute NMOSD attacks, particularly in patients with insufficient response to standard therapies. Given the absence of clinical worsening and the encouraging course observed in most of the patients, further investigation into the role of C5 inhibition in acute attack management is warranted.

CLASSIFICATION OF EVIDENCE: This retrospective case series provides Class IV evidence that the C5 complement inhibitors eculizumab or ravulizumab may improve disability in patients with NMOSD when given during or shortly after acute relapse.

A previously espoused notion that the brain is an immune-privileged organ has been challenged by evidence of bidirectional communication between the central nervous system and the periphery. A well-described "glymphatic" system in the brain and the meningeal lymphatic system serve as conduits through which antigens, immune cells, and metabolic waste travel from the brain to the deep cervical lymph nodes. These nodes, which are more than passive drainage points, serve as locales where dendritic cells, T cells, and B cells interact with central nervous system-derived signals and modulate immune responses that can influence the brain itself. Disruption of clearance mechanisms to deep cervical nodes-due to intracranial vascular disease, aging, poor sleep, chronic inflammation, or other etiologies-may lead to immune dysregulation. Abnormalities in lymphatic drainage can also alter the presentation of antigens from the central nervous system, affect lymphocyte trafficking, and contribute to the aggregation of proteins like β-amyloid, tau, and α-synuclein. This review synthesizes current knowledge on glymphatic and meningeal lymphatic anatomy and function, highlights how impaired drainage contributes to disorders including multiple sclerosis, Alzheimer disease, and Parkinson disease, and discusses the emerging role of deep cervical lymph node imaging and immunophenotyping in assessing neuroinflammation. Finally, we consider how modulation of meningeal lymphatic and nodal function, through pharmacologic or physical interventions, may impair or restore drainage and alter the course of disease in various ways. The integration of advanced imaging with immunological analysis ultimately may enhance the diagnosis, monitoring, and treatment of neuroinflammatory and neurodegenerative diseases. We propose that deep cervical lymph nodes represent an understudied locale, and, potentially, a therapeutic target for peripheral interventions to influence brain disease trajectories.

Despite advances in drug and device technology, health care delivery, and research infrastructure, cardiogenic shock (CS) continues to have nearly 50% in-hospital mortality. In patients with CS, both the initial severity of Society for Cardiovascular Angiography and Intervention CS and its subsequent trajectory predicts the clinical outcomes. Accordingly, delayed initial recognition and failure to escalate or deescalate treatment can significantly affect the outcomes of CS. Traditional assessment methods, with the exception of blood pressure measurement, require a high index of suspicion and frequent reassessment by the clinical team. Electronic medical record-based detection has been successfully implemented in acute and critical care patients with septic shock and acute kidney injury. In CS, electronic medical record-based studies have largely focused on using models to predict outcomes in patients with CS, with limited data on electronic medical record-based tools to assist with either predicting CS or providing real time alerts when escalation or de-escalation might be indicated. Early detection of CS may be associated with detection of earlier Society for Cardiovascular Angiography and Intervention stages of CS and potentially prevent deterioration to higher stages. In this review, we seek to highlight a blueprint for electronic medical record-based detection of CS that focuses on reproducibility, convenience, clinical decision support, and research aspects.

Clinical trials drive therapeutic innovation but often underrepresent populations most affected by the disease. Despite efforts to include women, minorities, and children, participation still lags behind intent. Ensuring equitable representation is essential to maximize the impact of new therapies. This perspective offers actionable insights from a diverse panel-including patients, clinicians, researchers, and advocates-shared during the 2025 American Society for Clinical Pharmacology and Therapeutics Patient Forum.

PURPOSE: We developed a dynamic B0 shimming approach using a 46-channel AC/DC shim array to correct phase errors caused by eddy currents from diffusion-encoding gradients in diffusion-prepared MRI, enabling high b value imaging without the SNR loss from the use of a magnitude stabilizer.

METHODS: A 46-channel AC/DC shim array and corresponding amplifier system were built. Spin echo prescans with and without diffusion preparation were then used to rapidly measure eddy current-induced phase differences. These phase maps were used as targets in an optimization framework to compute compensatory shim currents for multi-shot 3D diffusion-prepared acquisitions.

RESULTS: The proposed method allows flexible use of the AC/DC shim array to correct undesirable eddy current effects in diffusion-prepared MRI. Phantom and in vivo experiments demonstrate whole-brain, cardiac-gated, multi-shot 3D diffusion-prepared imaging without the use of magnitude stabilizers. The approach enables preservation of full SNR while achieving reliable diffusion encoding at b values up to 2000 s/mm2.

CONCLUSIONS: This work demonstrates a new strategy for applying an AC/DC shim array to compensate for eddy current-induced phase errors in diffusion-prepared MRI. By eliminating the need for a magnitude stabilizer, it enables efficient high-quality diffusion imaging with full signal sensitivity retained.

Immunotherapies revolutionized cancer treatment, yet their efficacy remains constrained by the tumor's immunosuppressive microenvironment. Here, we evaluated whether combining CD39 blockade with other modalities of immunotherapy such as IL-2/anti-IL-2 complexes (IL-2cx) administration could further enhance T cell-mediated antitumor responses and improve tumor control. We demonstrated that CD39 deficiency in MC38 tumor-bearing CD39KO (Entpd1 null) mice decreases tumor growth. This better tumor growth control was associated with increased infiltration of PD-1High CD8+ T cells, expressing elevated levels of exhaustion markers and transcription factors such as TOX. This PD-1High CD8+ T cell subset also exhibited a higher frequency of IFN-γ-producing and cytotoxic (Granzyme B+, Perforin+) cells. In contrast, the less immunogenic B16F10-OVA model did not show significant differences in tumor growth; however, CD39KO mice displayed an increased frequency of antigen-specific, pre-exhausted (PD-1Int) CD8+ T cells, a population recognized as a key target of immunotherapy. Pharmacological CD39 blockade with POM-1, when combined with IL-2cx treatment to redirect IL-2 activity, enhanced the accumulation of pre-exhausted CD8+ T cells with cytotoxic potential, thereby improving tumor control. This combinatorial strategy also reshaped the tumor immune landscape by increasing activated NK cells, elevating Granzyme B expression in CD4+ T cells, and decreasing immunosuppressive M-MDSCs expressing CD39, CD38, and CD73. Collectively, our findings demonstrate that integrating purinergic pathway inhibition with IL-2-based immunotherapies can coordinately reprogram lymphoid and myeloid compartments, attenuate immunosuppressive mechanisms within the tumor microenvironment, and amplify antitumor immunity, providing a strong rationale for advancing this strategy toward clinical translation.

Endocrine and exocrine insufficiencies are well-recognized pancreatic-specific sequelae of chronic pancreatitis (CP), yet the impact of CP extends beyond the pancreas. The pathophysiology driving these complications is complex and poorly understood, resulting in inadequate recognition and an inability to stratify risk of disease progression. To address this topic, the Collaborative Alliance for Pancreatic Education and Research convened a workshop to summarize our current understanding and identify knowledge gaps related to the complications of CP. The clinical uncertainty related to who will develop systemic complications of CP, and when, negatively affects the patient's clinical experience and is an area of research that requires additional commitment. Adapting modeling strategies proven effective in other conditions (eg, type 2 diabetes) may be effective in identifying and predicting the onset of endocrine and exocrine insufficiencies. Improved understanding related to genetic risk factors, biomarkers, clinical testing, and advanced imaging techniques all represent pathways to better identify these complications and develop pancreatitis-specific interventions. Additional complications of CP, including pain, osteopathies, sarcopenia, malnutrition, and visceral neuropathies, can occur independently or as complications from endocrine and/or exocrine insufficiency. Better screening strategies to identify these conditions are required, many of which may be accomplished using opportunistic screening strategies. Future research will need to utilize existing treatment modalities and medications, in addition to developing new interventions, to treat these complications of CP that have a tremendous impact on patients' quality of life. Genetic testing in pancreatitis is likely to inform any research related to the complications of CP, but low penetrance of disease, poor genotype-phenotype associations, and health disparities that impact the use of testing across centers currently limit its clinical utility for all patients. Genetic testing remains critical in certain populations with CP and should be incorporated into research whenever possible to inform much-needed disease progression prediction models.

To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.