Faculty Bibliography

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.

IMPORTANCE/UNASSIGNED:Guideline-discordant care for acute low back pain (aLBP) is common and has been associated with adverse outcomes. OBJECTIVES/UNASSIGNED:To estimate the incidence of new opioid use disorder (OUD) or overdose diagnosis among opioid-naive patients with Medicaid coverage initiating treatment for aLBP and to evaluate the association between initial treatment modalities and subsequent risk of OUD or overdose diagnosis. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from January 1, 2016, to December 31, 2019, with 13 months of follow-up (1-month exposure assessment followed by 12 months of outcome follow-up) from the Transformed Medicaid Statistical Information System Analytic Files from 25 states that expanded Medicaid under the Patient Protection and Affordable Care Act by 2014. Participants included opioid-naive, adults aged less than 65 years who received pain treatment within 1 month of diagnosis of aLBP. Data were analyzed from March 1, 2025, to July 31, 2026. EXPOSURES/UNASSIGNED:Initial pharmacologic and nonpharmacologic treatments for aLBP. MAIN OUTCOMES AND MEASURES/UNASSIGNED:OUD or overdose diagnosis, defined using diagnostic codes for opioid abuse, opioid dependence, opioid-involved overdose, or a prescription for medication for treating OUD. RESULTS/UNASSIGNED:In this cohort of  399 500 Medicaid patients who initiated treatment for newly diagnosed aLBP, the median age was 39 (IQR, 30-50) years, and 237 846 (59.5%) were female. The cumulative incidence of OUD or overdose diagnosis was 1.4% at 7 months and 2.3% at 13 months. Initiating vs not initiating higher-dose opioids (>50 mg of morphine equivalent) as part of the initial treatment was associated with the greatest risk, increasing risk of OUD or overdose by 146.6% (95% CI, 121.5%-171.7%). Initiating vs not initiating lower-dose opioids prescribed for more than 7 days or gabapentinoids each increased risk by 105.2% (95% CI, 89.0%-121.4%) and 101.6% (95% CI, 84.9%-118.2%), respectively. Nonpharmacologic, noninterventional therapies were associated with reductions in risk of OUD or overdose diagnosis. Initiating vs not initiating chiropractic care was associated with the largest relative risk reduction, decreasing risk by 32.8% (95% CI, 26.8%-38.9%), and initiating physical therapy was associated with 31.1% decreased risk (95% CI, 22.1%-40.1%). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, nonpharmacologic, noninterventional treatment was associated with reductions in risk of OUD or overdose diagnosis while initiating treatment with opioids or gabapentinoids was each associated with higher risks. These results support guideline recommendations favoring nonpharmacologic treatments as first-line therapy for aLBP.

Can the transcriptomic profile of a neuron predict its physiological properties? Using a Patch-seq dataset of the primary visual cortex, we addressed this question by focusing on spike rate adaptation (SRA), a well-known phenomenon that depends on small conductance calcium (Ca)-dependent potassium (SK) channels. We first show that in parvalbumin-expressing (PV) and somatostatin-expressing (SST) interneurons, expression levels of genes encoding the ion channels underlying action potential generation are correlated with the half-width (HW) of spikes. Surprisingly, the SK encoding genes are not correlated with the degree of SRA (dAdap). Instead, genes that encode proteins upstream from the SK current, as well as the low-voltage-activated calcium channel, are correlated with dAdap. This general principle is supported by datasets from the mouse primary motor cortex and multiple macaque brain regions. Finally, we generate testable predictions by constructing a minimal computational model.

Tafazzin is a phospholipid-lysophospholipid acyltransferase that remodels fatty acids of mitochondrial phospholipids. To study the tafazzin mechanism, we expressed and purified the enzyme, measured its kinetics with different pairs of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species, and simulated the reactions in a mathematical model based on the mass-action law. Variations in chain length and PC:LPC ratio showed that tafazzin reacts with micelles but not with bilayers. In the presence of micellar substrates (LPC + short-chain PC), transacylation rates measured at different substrate ratios suggested similar affinities for PC and LPC. Surprisingly, tafazzin catalyzed both transacylation and hydrolysis of fatty acids, the former preferring oleoyl over palmitoyl and the latter preferring palmitoyl over oleoyl groups. To study the remodeling of cardiolipin, we measured the reaction of trilinoleoyl-monolyso-cardiolipin with palmitoyl-oleoyl-PC and simulated it in a mathematical model. Simulations predicted and measurements confirmed a large number of bidirectional transacylations between the initial substrates, between substrates and products, and between different products. This led to a gradual diversification of the lipid composition from 2 to more than 15 species. Discrepancies between observed and simulated compositions demonstrated transacylation preference for oleoyl over palmitoyl groups. The data are consistent with a bidirectional ping-pong mechanism that operates through a single low-affinity binding site and suggest that transacylation specificity can at least in part be explained by selective loss of fatty acids through hydrolysis.

BACKGROUND:Although gliomas during pregnancy are rare, they present significant clinical and ethical challenges due to the potential effects of pregnancy on tumor behavior and the risks associated with the standard of care. Given the peak incidence of IDH-mutant glioma in the 3rd and 4th decades of life, clinicians face a challenge in balancing maternal oncological outcomes with fetal safety, while navigating the uncertainty surrounding the effects of standard treatment modalities on fetal development. OBSERVATIONS/METHODS:A 31-year-old woman at 23 weeks of gestation with a history of IDH-mutant glioma presented to the authors' institution with worsening neurological symptoms. MRI indicated tumor progression, and re-resection was performed via awake craniotomy with functional mapping. The maternal-fetal medicine team was consulted to guide the selection of anesthesia and optimize intraoperative positioning, ensuring the safety of both the patient and fetus. Postoperative recovery was uneventful, with stable maternal and fetal outcomes. Pathological analysis confirmed progression to a grade 4 astrocytoma. LESSONS/CONCLUSIONS:This case highlights the feasibility of awake craniotomy with functional mapping during pregnancy. Management of gliomas in pregnancy requires a multidisciplinary approach, balancing maternal health and fetal safety, with careful consideration of treatment timing and anesthetic strategies. https://thejns.org/doi/10.3171/CASE2696.

BACKGROUND:Fewer than 20% of donated lungs are transplanted. We examined the impacts of donor management and recovery at an in-hospital donor care unit (DCU) established in 2021 versus the donor hospital (DH). METHODS:(P/F ratio) were examined as a hypothesized effect modifier. We projected the national impact of improved utilization on lung transplant volume. RESULTS:After adjusting for donor differences, lung utilization was 88% higher (aRR: 1.88; 95% CI: 1.40, 2.53) in the DCU versus DH setting. Median P/F ratio increased from 275 to 348 mmHg (p<0.0001) in the DCU and explained approximately 38% of the improvement in lung utilization. Non-lung organ utilization was either improved or non-inferior in the DCU. Lung graft survival and pulmonary function were similar for recipients of DCU versus DH-managed donors. Nationally, an 88% improvement in lung utilization among donors not currently transferred to a DCU could theoretically result in ≥300 more lung transplants per year. CONCLUSIONS:Lung transplantation can be nearly doubled through lung-centric donor management in a DCU, without sacrificing recipient outcomes nor the utilization of other organs. Donor management practices to optimize lung utilization should be proliferated by establishing more DCUs and, where feasible, applying lung-centric protocols in donor hospitals.

BACKGROUND:Fast-track (FT) protocol is an established but not standardized approach in cardiac surgery. We aimed to describe our FT protocol and to compare outcomes before and after the protocol implementation (non-FT group and FT group, respectively). METHODS:Fast-track protocol was implemented in March 2021 in our institution. All patients who underwent median sternotomy from January 2018 to June 2024 were identified. Patient characteristics and outcomes were compared between the FT group and non-FT group, using propensity-score matching. RESULTS:A total of 456 patients, primarily aortic valve replacement, mitral valve repair or replacement, and root and ascending aortic surgery, were included. Of 456, 261 patients were the FT group and 195 patients were the non-FT group. In the FT group, 91.6% of patients were extubated in the OR (vs. 42.1% in the non-FT group, p < 0.001). In the FT group, 193 (73.9%) were discharged within 2 or 3 days after surgery. After propensity-score matching, the median hospital length of stays (LOS) was significantly shorter in the FT group (3 days vs. 4 days, p < 0.001). Baseline characteristics, operations, and perioperative outcomes were similar between the groups, including 30-day mortality (0.5% vs. 0.5%, p = 1.0), prolonged ventilation (1.1% vs. 1.1%, p = 1.0), discharge to home (1.6% vs. 2.2%, p = 0.72), and readmission (3.8% vs. 4.3%, p = 0.80). CONCLUSIONS:The FT protocol was associated with decreased hospital LOS. Additionally, this study suggested that discharge within 3 postoperative days is feasible after most valve surgeries.

Kidneys from donation after circulatory death (DCD) donors historically had lower recovery and utilization than kidneys from donation after brain death (DBD) donors. However, the organ shortage and advances in organ preservation have increased interest in DCD transplantation. We used OPTN data to study temporal changes in U.S. DCD kidney recovery and transplantation. The percent DCD among kidney donors increased from 21.0% (Era1: 2016-2019) to 30.6% (Era2: 2020-2022) and 42.4% (Era3: 2023-2025). By 2025Q2, more than half (50.4%) of kidney donors were DCDs. Wide variability persisted across eras in percent DCD by recovering OPO (Era1 range: 0%-38%, Era2: 0%-49%, Era3: 0.4%-60%) and by transplanting center (Era1 range: 0%-48%, Era2: 0%-58%, Era3: 0%-60%). Transplanted DCD kidneys in Era3 (vs Era1 & Era2) were more likely to have donor age >60, diabetes, hypertension, obesity, and death due to cardiovascular disease or stroke; 86.8% were pumped. Though the recovered DCD kidney nonuse rate rose from 20.8% (Era1) to 29.9% (Era2) and 35.4% (Era3), nonused DCD kidney donors were age and had more comorbidities in Era 3 compared to earlier eras. Given that half of kidney donors are now DCD, refinements in DCD donor selection and management are needed to optimize recovery and utilization.

BACKGROUND:Degenerative disc disease (DDD) with cartilaginous endplate degeneration and Modic type 1 or 2 changes is increasingly recognized as a source of chronic vertebrogenic and discogenic low back pain. Because the intervertebral disc and vertebral endplates function as a biological and biomechanical unit, regenerative strategies targeting both structures may better address the disc-endplate complex. CASE SERIES/METHODS:Thirteen consecutive patients with chronic refractory vertebrogenic and/or discogenic low back pain, MRI evidence of DDD with Modic type 1 or 2 changes, and failure of conservative management underwent combined intradiscal, peridiscal, and subchondral bone marrow aspirate concentrate (BMAC) injections under fluoroscopic guidance. Four patients had previously undergone basivertebral nerve radiofrequency ablation. The cohort included 6 men and 7 women with a mean age of 56.2 ± 17.5 years. Follow-up ranged from 4 to 15 months. Mean Visual Analog Scale scores decreased from 7.3 ± 2.0 at baseline to 2.1 ± 1.6 at latest follow-up, a mean reduction of 5.2 ± 1.8 points (72.7% ± 19.5%). All patients achieved at least 50% pain reduction and reported functional improvement. Twelve patients (92.3%) were satisfied or very satisfied, and all would recommend the procedure. No major procedure-related complications were observed. CONCLUSION/CONCLUSIONS:Combined intradiscal, peridiscal, and subchondral BMAC injections were associated with substantial pain reduction, functional improvement, high patient satisfaction, and no major complications in this small retrospective case series. Larger prospective controlled studies are needed to confirm these preliminary findings.

Interventional procedures that target the sympathetic nervous system and specific autonomic and sensory ganglia are widely used for refractory visceral, neuropathic, and cancer-related pain. They can provide substantial, often durable analgesia but carry a small yet clinically important risk of serious adverse events. This is the third part of our narrative-review series on the safety of interventional pain procedures, following Part 1 (spinal pain injections) and Part 2 (procedures for back pain), both published in the Journal of Pain Research. It is a structured but non-systematic narrative review (PubMed, Scopus, Embase, and the Cochrane Library; 1980-2026). We examine the complications of image-guided and neuroablative procedures directed at the trigeminal (Gasserian), sphenopalatine, stellate, thoracic sympathetic, celiac/splanchnic, lumbar sympathetic, superior and inferior hypogastric, and impar ganglia and plexuses; we outline the pharmacology of phenol and ethanol and compare them with conventional radiofrequency and cryoneurolysis. Most reported complications are mild, self-limiting, and physiologically predictable, such as hypotension, diarrhea, transient sensory change, and Horner syndrome. Serious events-paraplegia, spinal cord infarction, retropharyngeal hematoma, meningitis, visceral perforation, and anesthesia dolorosa-appear uncommon, but their true incidence remains uncertain and varies by procedure, and much of the evidence derives from isolated case reports. They reflect either anatomical proximity to critical neurovascular structures or unintended spread of the neurolytic agent. Across techniques, the determinants of safety comprise real-time image guidance, meticulous needle placement, incremental dosing, contrast confirmation, attention to anticoagulation status, and careful patient selection.