Faculty Bibliography

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.

Background Obesity is a global epidemic. The prevalence of obesity has significantly increased in recent decades and is expected to impact a large portion of the US population. Hypertension continues to be one of the most common complications associated with obesity, and the overlap between these two conditions has been growing over time. However, mortality trends in patients with obesity and hypertension have not been investigated in the literature. Objectives This study aimed to investigate mortality trends, stratified by sex, race, age groups, and geographic distribution, in the US population between 1999 and 2020. Methods Death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) were examined and analyzed between 1999 and 2020 for patients with obesity and hypertension as the contributing causes of death. The age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) per 100000 people were calculated by sex, race, age group, and geographic region. Results Among individuals aged ≥15, a total of 294854 deaths occurred in individuals with obesity and hypertension between 1999 and 2020. The overall AAMR increased from 1.08 in 1999 to 12.14 in 2020. The AAMR has steadily increased since 1999, with a sudden spike occurring between 2018 and 2020 during the COVID-19 pandemic. This trend has been observed across nearly all variables analyzed in our study. Our results exhibited a 28% increase in mortality related to obesity and hypertension during the early years of the COVID-19 pandemic. During the study period, men had a higher overall AAMR than women (men, 5.92; women, 4.32). Mortality was highest among the 55-74-year-old age group, followed by the 75-plus-year-old, 35-54-year-old, and finally 15-34-year-old age groups, which displayed the lowest AAMR (AAMR: 55-74, 11.76; 75+, 10.83; 35-54, 4.73; and 15-34, 0.54). Among the races, non-Hispanic (NH) Blacks had the highest overall AAMR (9.81), followed by NH American Indians or Alaskan Natives (6.01), NH Whites (4.64), Hispanics (4.08), and NH Asians or Pacific Islanders (1.17). However, NH Whites showed the highest average APC (AAPC) (11.44), indicating a possible future shift in mortality. By geographic region, the Southern United States had the highest AAMR, followed by the Western, Midwestern, and Northeastern regions. Non-metropolitan areas had consistently higher obesity- and hypertension-related AAMRs (5.63 overall) compared to metropolitan areas (4.99 overall). Conclusion In our retrospective analysis of death certificate data from 1999 to 2020, we found that age-adjusted mortality rates among individuals with both obesity and hypertension consistently displayed an increasing trend across all demographic groups. The overall rising AAMRs, compounded by the disproportionately high average annual percent changes among White individuals and those aged 15-34, raise serious concerns for the healthcare system. These findings have significant implications for public health policy. Focused interventions are essential to curb the upward trajectory of mortality in this population, as early intervention can greatly help tackle the dual burden of obesity and hypertension, which are largely preventable.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

Cefdinir is a third-generation cephalosporin with a wide variety of indications and a strong safety profile. A 24-year-old man began taking cefdinir for an uncomplicated urinary tract infection. Two days later, he began experiencing pleuritic, sharp chest pain and diarrhea and was shown to have mildly elevated troponins. Due to the pleuritic nature of his chest pain improving when leaning forward, as well as elevated troponins and a new small pericardial effusion on echocardiogram, he was diagnosed with myopericarditis thought to be secondary to cefdinir. Cefdinir was subsequently held with diarrhea and chest pain improving shortly afterwards. He was started on ibuprofen 600mg TID for two weeks, as well as colchicine 0.5mg daily for six weeks. The patient finished his treatment regimen and does not endorse recurrence of his chest pain or any symptoms of heart failure, such as orthopnea, lower extremity edema, or shortness of breath.

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.

BACKGROUND/UNASSIGNED:Risankizumab is used for prolongated duration by patients, necessitating further research to characterize the infectious risks involved. CASE PRESENTATION/UNASSIGNED:three weeks after collection. The patient ultimately completed two weeks of oral doxycycline. CONCLUSION/UNASSIGNED:Given the lack of notable risk factors for lung abscess, this case suggests a possible association with Risankizumab, which may have contributed to immunosuppression.

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.

Mitochondria are critical cellular powerhouses that produce adenosine triphosphate to maintain the structure and integrity of the cell. Mitochondria generate 90% of the energy of a cell. Chronic inflammation causes damage to mitochondria. When enough mitochondria are dysfunctional, the involved organ will suffer. Mitochondria become dysfunctional in the setting of chronic inflammation. Under noninflammatory conditions, the body generates new mitochondria (mitochondrial biogenesis) and removes old and damaged mitochondria via mitophagy. When mitochondria are damaged, they "spontaneously" leak out reactive oxygen species, mitochondrial DNA, and damage-associated molecular patterns, generating erroneous innate immune responses. Autophagy is a recycling and housekeeping process that removes dysfunctional components, organelles, and proteins, promoting the recovery and maintenance of cell health. Mitophagy is a specific variant of this process that removes dysfunctional mitochondria from the cell. Mitophagy declines with age, allowing dysfunctional mitochondria to accumulate, and chronic inflammation leads to cardiovascular disease (CVD). In CVD, impairment of both autophagy and mitophagy leads to more chronic inflammation, characterized by hyperactivation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a key component of the immune system. Once activated, it triggers inflammation, leading to excessive cytokine activity, proinflammatory macrophage polarization, pyroptosis, and increased immune cell infiltration into cardiac and vascular tissues. Pyroptosis is a form of inflammatory cell death triggered by programmed cues; however, in autoimmunity and cancer, when overactivated, this process can become detrimental. Adequate regulation of these events reduces oxidative stress, inflammatory cascades, fibrosis, and maladaptive remodeling, thereby improving overall cardiovascular health. Targeted therapeutic enhancement of autophagy and mitophagy represents a promising strategy to modulate immune-driven pathology and improve outcomes in cardiovascular conditions. We will review the mechanisms of how this inflammation causes CVD.

INTRODUCTION/BACKGROUND:Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown. METHODS:CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, Aβ42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change. RESULTS:Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (β = 0.28, 95% confidence interval [CI] [0.11, 0.45]) but not Aβ42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction β = 0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (β = 0.13, 95% CI [0.08, 0.18]). DISCUSSION/CONCLUSIONS:CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.