Faculty Bibliography

OBJECTIVES/OBJECTIVE:Propofol is used sparingly in pediatrics owing to the risk of propofol-related infusion syndrome (PRIS). The objective of this study is to evaluate the safety of propofol in pediatrics and describe its effectiveness at facilitating extubation and decreasing concomitant sedation. METHODS:This retrospective, descriptive study evaluated critically ill children who received continuous propofol infusions for at least 12 consecutive hours while admitted to pediatric, congenital cardiac, or neonatal intensive care units. The primary outcome was PRIS incidence. Secondary outcomes included change from baseline in laboratory parameters, discontinuation due to adverse effects, change in sedative requirements following sedation washout, and successful extubation. RESULTS:From January 1, 2019, to November 1, 2023, a total of 100 children received 120 courses of propofol infusions. The median infusion rate was 106 mcg/kg/min (IQR, 68-149) and 27.5% of courses exceeded 48 hours in duration. No PRIS events were identified. Patients experienced a moderate, non-duration-dependent increase in triglycerides, with no impact on aspartate aminotransferase (AST)/alanine aminotransferase (ALT) concentrations; 11.7% of infusions were discontinued for adverse effects. No children self-extubated while on propofol when used for peri-extubation (N = 49). Opioid and benzodiazepine requirements were decreased by 17% and 26% from baseline, respectively, during a 24-hour period following sedation washout (N = 26). CONCLUSIONS:Propofol was tolerated by most patients at doses commonly exceeding guideline-recommended maximum rate and duration. Propofol was safely used to facilitate extubation and decreased baseline sedative exposure when used for sedation washout in a complex critically ill pediatric population.

BACKGROUND:: The glioblastoma (GBM) immunosuppressive tumor microenvironment is a clinical challenge. Oncolytic Zika virus (ZIKV) has emerged as a promising therapy, targeting treatment-resistant glioma stem cells, stimulating CD8+ T-cell-mediated immunity and extends survival in preclinical models but myeloid cell-driven immunosuppression persists. An antagonist of Siglec-15, a myeloid immune checkpoint molecule, is in a phase II trial for non-small cell lung cancer, but its role in CNS malignancies remains unclear. METHODS:: We evaluated Siglec-15 expression in human GBM samples using flow cytometry, mass cytometry, and immunofluorescence, as well as a public database. Using syngeneic glioma models, we tested a blocking antibody against Siglec-15, and Siglec-15 knock out mice, alongside ZIKV and anti-PD-1 therapies. We performed survival studies and analyzed immune responses, T-cell proliferation and phagocytosis, and tumor rechallenge. RESULTS:: Siglec-15 was expressed by human GBM myeloid (16-22%) and tumor (18-19%) cells, and higher expression was associated with shorter survival. In CT2A-bearing mice, ZIKV + anti-Siglec-15 increased long-term survival to 60% (vs. 40% with ZIKV alone), rising to 83% with anti-PD-1 treatment. Triple therapy in SB28 bearing mice yielded 76% long-term survivor rate with 1.7-fold higher CD8+ T-cell activation. Rechallenged mice showed 11-fold expansion of brain resident/effector memory CD8+ T-cells and 80% survival. Siglec-15 loss on myeloid cells enhanced phagocytosis (CT2A: 25%; SB28: 7%) and T-cell responses (activation: 81%; proliferation: 86.8%). CONCLUSION/CONCLUSIONS:: Targeting Siglec-15, combined with PD-1 blockade and ZIKV overcomes myeloid immunosuppression and enhances T-cell activation in GBM, promoting durable anti-tumor immunity. These findings support further investigation of this combination therapy.

OBJECTIVES/OBJECTIVE:Retained placenta is a potential complication of second-trimester induction of labour. There is limited consensus regarding the use of adjunctive medications to manage the third stage following second-trimester vaginal delivery. This study aimed to evaluate the effects of oxytocin versus misoprostol on third-stage duration and the need for dilation and curettage (D&C) among patients with and without mifepristone pretreatment. STUDY DESIGN/METHODS:We conducted a retrospective cohort study of patients undergoing induction of labour between 14 + 0 and 23 + 6 weeks of gestation for any indication. Data on third-stage uterotonic use and mifepristone pre-treatment were collected. Primary outcomes were third-stage duration and the need for D&C for retained placenta among patients who received a third-stage uterotonic agent. Associations were assessed using adjusted linear and logistic regression models controlling for relevant clinical covariates. RESULTS:Among 181 patients, 85 (47.0%) received a third-stage uterotonic (oxytocin n = 55, 30.4%; misoprostol n = 45, 24.9%) and 101 (55.8%) received mifepristone (median 4.6 h prior to induction). Among patients receiving a third-stage uterotonic, oxytocin use was associated with a 2-hour reduction in placental delivery time and a 74% lower likelihood of D&C compared with misoprostol. Mifepristone pretreatment was not associated with third-stage duration (10 vs 24.5 min, p = 0.43) or D&C rates (12.9% vs 13.8%, p = 0.86). CONCLUSIONS:When third-stage uterotonic intervention is required following second-trimester induction of labour, oxytocin is associated with significantly shorter placental delivery time and lower likelihood of D&C when compared with misoprostol. Mifepristone pretreatment shortly before induction appears to have minimal impact on third-stage outcomes.

INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by the progressive loss of muscle control, leading to paralysis and death. While ALS has been extensively studied globally, little research has focused on ALS in the Middle East, specifically Saudi Arabia. This study aims to investigate the demographic data, clinical characteristics, disease progression, and prognosis of ALS patients in Saudi Arabia to better understand region-specific disease patterns and potential therapeutic strategies. METHODOLOGY:Retrospective multicenter cohort across five tertiary Saudi centers (2003-2022). The authors identified cases from neurology/neuromuscular clinics and neurophysiology laboratories; diagnoses followed revised El Escorial criteria with EMG confirmation where indicated. ALS variants and cases lacking sufficient longitudinal evidence were excluded. Clinical genetic testing was performed at the clinician's discretion; variants were classified per ACMG and only pathogenic/likely pathogenic results were counted; C9orf72 repeat-expansion testing was not systematically available. Prespecified variables included demographics, family history, initial phenotype, MRI/EMG, genetics, treatments (riluzole, edaravone, SPT, tofersen for SOD1), times to noninvasive ventilation (NIV), gastrostomy and invasive ventilation. RESULTS:We included 270 patients (57% male). Mean age at first symptom was 51 years. Limb-onset occurred in 169/247 (68%) and bulbar-onset in 78/247 (32%). Among those with documented family history (97/270), 14% reported an affected relative. 37/270 underwent genetic testing; 56.7% were positive-most commonly OPTN (47.6.6% of positives) and SOD1 (38.1%). MRI brain/spine was normal in ∼53%. By 3 years from symptom onset, ∼80% of those who eventually required advanced support (NIV, invasive ventilation, and/or gastrostomy) had received it. Most patients were treated with riluzole. CONCLUSION:This study provides valuable insights into ALS in Saudi Arabia, contributing to a better understanding of the disease in this region. The younger age of onset and the high familial prevalence are notable findings that warrant further investigation. Future studies focusing on genetic and environmental influences in Saudi Arabia may help improve diagnosis and therapeutic approaches.

BACKGROUND:Hemorrhage is the leading cause of preventable death world-wide. Traumatic brain injury (TBI) is the primary driver of mortality and morbidity among individuals aged 1-44 years worldwide, with intracranial hemorrhage (ICH) being the major contributor to acute mortality post-TBI. Based on prior studies, we hypothesized that lyophilized platelet-derived extracellular vesicles (LPEVs) would reduce ICH and preserve blood-brain barrier (BBB) integrity after TBI. METHODS:LPEVs were characterized by flow cytometry, scanning electron microscopy, and Nanosight. LPEVs were evaluated in vitro in human brain endothelial cell monolayers for barrier integrity. Utilizing a murine TBI model of controlled cortical impact, LPEVs were transfused 40 min after injury. The degree of BBB permeability was quantitated by 10kD infrared-tagged dye that leakage into the brain. ICH was quantitated by RBCs using Ter-119 antibody. Murine tail snip and cremaster muscle vascular injury models and thromboelastography analysis of healthy donor or trauma patient blood were used to assess hemostatic ability of LPEVs. Proteomic content was analyzed by mass spectrometry and mRNA and miRNA content by next-generation sequencing. Light transmission aggregometry using fresh apheresis platelets or generated dysfunctional platelets supported the mechanistic pathway assessment. RESULTS:LPEVs were predominantly in the exosome range, expressed platelet and microvesicle markers and generated thrombin. In vitro, LPEVs attenuated thrombin-induced paracellular permeability and reduced intercellular gaps in human brain microvascular endothelial cells. In vivo, LPEVs exhibited potent hemostatic activity in a murine tail-transection and cremaster vascular injury models. Following experimental TBI in mice, acute administration of LPEVs significantly reduced ICH without impacting BBB permeability. Multi-omics analyses revealed that LPEVs retained platelet-derived hemostatic cargo, but lacked the vasculoprotective factors, typically present in intact platelets. LPEVs accelerated clot formation in blood from healthy donors, trauma patients, and dysfunctional platelet preparations. Mechanistically, LPEVs promote hemostasis in part through GPIIb/IIIa-dependent platelet aggregation. CONCLUSIONS:These data demonstrate the therapeutic and hemostatic efficacy of LPEVs in reducing ICH following TBI without affecting BBB permeability or neuroinflammation. The multi-omics and GPIIB/IIIA driven data can potentially explain the decoupled effects of LPEVs on hemostasis and vascular permeability in our experimental TBI model.

Women with a history of surgical correction for adolescent idiopathic scoliosis are often denied neuraxial anesthesia during labor and delivery due to concerns of technical difficulties, anesthetic failures, inadvertent dural punctures, and hardware infections. We report four successful neuraxial procedures by four different anesthesiologists in three patients with previous posterior spinal instrumentation and fusion who delivered at our institution. The procedures include spinal anesthesia for cerclage, epidural analgesia for labor followed by successful conversion to epidural anesthesia for intrapartum cesarean delivery, spinal anesthesia for cesarean delivery, and epidural analgesia for vaginal delivery. Modern surgical techniques improve success rates of neuraxial anesthesia. Antenatal anesthesia consultation, knowledge of the lowest instrumented vertebra, familiarity with neuraxial ultrasound and multidisciplinary collaboration between orthopedic, obstetric, and anesthesiology teams are key. Anesthesiologists should offer and attempt neuraxial anesthesia if desired by these patients. Neuraxial anesthesia should not be withheld from them because they have spine instrumentation.

Myeloproliferative neoplasms (MPNs) are a spectrum of clonal hematologic malignancies, characterized by an acquired somatic mutation in hematopoietic stem cells (HSC). Consequent constitutive activation of the JAK/STAT signaling pathway ultimately leads to HSC clonal expansion, a heightened inflammatory state, and aberrant trafficking of the malignant stem cells to sites of extramedullary hematopoiesis. While polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are distinct disease entities, each with their own diagnostic criteria, risk stratification, and molecular profiles, they share a common pathogenesis and exist on a spectrum, with overlapping clinical features, propensity for thrombohemorrhagic events, and risk for transformation to acute leukemia. Interferon alpha (IFN-α) has both anti-proliferative and immunomodulatory effects on MPN HSCs, and therefore is an effective treatment modality for PV, ET, and MF. In this review, we discuss the rationale for IFN-α use in MPNs, examine the evidence supporting its use, and convey practical considerations.

STUDY DESIGN/METHODS:Retrospective cohort study. OBJECTIVE:To evaluate the association between paraspinal interfascial plane (PIP) block use and postoperative outcomes and resource utilization in posterior lumbar spine surgery. SUMMARY OF BACKGROUND DATA/BACKGROUND:The PIP block is a regional anesthesia technique that may improve pain control after posterior spine surgery, but its impact on outcomes remains underreported in large cohorts. METHODS:We retrospectively reviewed 327 age-matched adult patients who underwent posterior lumbar surgery between October 2020 and June 2024. Of these, 164 received a PIP block, and 163 did not. Primary outcomes included postoperative opioid consumption and pain scores. Secondary outcomes included hospital length of stay, ICU admission, postoperative nausea and vomiting, and estimated blood loss. RESULTS:The PIP group had lower opioid use in the first 24 hours postoperatively (median: 0.83 vs. 0.98 MME/kg, P=0.046) and a trend toward reduced use from 24-48 hours (median: 0.39 vs. 0.46 MME/kg, P=0.067). The median pain scores at 0-24 hours were similar (7.0 vs. 7.5, P>0.9), but were significantly lower at 24-48 hours (P=0.03). Hospital length of stay was shorter in the PIP group (median: 4.0 vs. 5.0 d, P<0.001), and postoperative nausea and vomiting were less frequent (8.8% vs. 21%, P=0.002). The time to first analgesic request was delayed within the first 250 minutes postoperatively in the PIP group (P=0.042). ICU admission and estimated blood loss did not differ between groups. CONCLUSIONS:Use of the paraspinal interfascial plane block in posterior lumbar spine surgery was associated with reduced early postoperative opioid consumption, decreased length of stay, and less postoperative nausea and vomiting. These findings support the potential value of the PIP block as an adjunct to multimodal analgesia protocols in posterior lumbar spine surgery. LEVEL OF EVIDENCE/METHODS:Level III.

INTRODUCTION/UNASSIGNED:negative myeloproliferative neoplasm (MPN) driven by recurrent acquired somatic mutations in hematopoietic stem cells and characterized by progressive bone marrow fibrosis, cytopenias, and extramedullary hematopoiesis. Janus kinase inhibitors (JAKi) improve splenomegaly and MF symptom burden but without achieving molecular remission or clear disease course modification. Novel therapies targeting epigenetic dysregulation through bromodomain and extra-terminal domain (BET) proteins have emerged as a key therapeutic approach, aimed at reducing pro-inflammatory and oncogenic transcription to deepen clinical responses in combination with JAKi therapy. AREAS COVERED/UNASSIGNED:This review summarizes the biology, preclinical data, and emerging clinical data in the development of novel BET inhibitor (BETi). Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. EXPERT OPINION/UNASSIGNED:BET protein inhibition is a promising therapeutic target complementing JAK inhibition by co-targeting inflammatory pathways, fibrosis, and clonal proliferation. Pelabresib is a pan-BETi furthest in development demonstrating clinical benefit with ongoing trials. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies is ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.