Trends and Rates of Reporting of Race, Ethnicity, and Social Determinants of Health in Spine Surgery Randomized Clinical Trials: A Systematic Review.

STUDY DESIGN: A systematic review. OBJECTIVE: We characterized the rates of sociodemographic data and social determinants of health (SDOH) reported in spinal surgery randomized control trials (RCTs) and the association between these RCTs' characteristics and their rates of reporting on race, ethnicity, and SDOH variables. SUMMARY OF BACKGROUND DATA: Although numerous institutions maintain guidelines and recommendations regarding the inclusion and reporting of sociodemographic and SDOH variables in RCTs, the proportion of studies that ultimately report such information is unclear, particularly in spine surgery. MATERIALS AND METHODS: We searched the MEDLINE, PubMed, and Embase databases for published results from spinal surgery RCTs from January 2002 through December 2022, and screened studies according to prespecified inclusion criteria regarding analysis and reporting of sociodemographic and SDOH variables. RESULTS: We analyzed 421 studies. Ninety-six studies (22.8%) reported race, ethnicity, or SDOH covariates. On multivariate analysis, study size [rate ratio (RR)=1.18; 95% CI, 1.06-1.32], public/institutional funding (RR=2.28; 95% CI, 1.29-4.04), and private funding (RR=3.27; 95% CI, 1.87-5.74) were significantly associated with reporting race, ethnicity, or SDOH variables. Study size (RR=1.26; 95% CI, 1.07-1.48) and North American region (RR=21.84; CI, 5.04-94.64) were associated with a higher probability of reporting race and/or ethnicity. Finally, study size (RR=1.27; 95% CI, 1.10-1.46), public/institutional funding (RR=2.68; 95% CI, 1.33-5.39), focus on rehabilitation/therapy intervention (RR=2.70; 95% CI, 1.40-5.21), and nonblinded study groups (RR=2.70; 95% CI, 1.40-5.21) were associated with significantly higher probability of reporting employment status. CONCLUSION: Rates of reporting race, ethnicity, and SDOH variables were lower in the spinal surgery RCTs in our study than in RCTs in other medical disciplines. These reporting rates did not increase over a 20-year period. Trial characteristics significantly associated with higher rates of reporting were larger study size, North American region, private or public funding, and a focus on behavioral/rehabilitation interventions. LEVEL OF EVIDENCE: Level III.

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma.

Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

Rapid tumor DNA analysis of cerebrospinal fluid accelerates treatment of central nervous system lymphoma.

ABSTRACT: Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Radical surgical resection with molecular margins is associated with improved survival in IDH wild-type glioblastoma.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of postsurgical progressive events are failures within 2 cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBMs are amenable to radiographic gross-total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an area under the curve of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found that 89% of patients were correctly predicted to achieve a residual volume (RV) < 4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a GTR (RV < 1cc). In these 5 patients at 30 months follow-up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (P = .02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefits from radical resection to undetectable molecular margins.

Gender diversity at spine surgery academic conferences: a 15-year investigation.

BACKGROUND CONTEXT: Enhancing gender diversity at academic conferences is critical for advancing women's representation and career trajectories in spine surgery. PURPOSE: To discover trends in women's representation at major spine conferences over a 15-year period. STUDY DESIGN/SETTING: Conference records from the 2007-2021 annual meetings of the Congress of Neurological Surgeons, North American Spine Society, and Scoliosis Research Society (SRS). PATIENT SAMPLE: Authors of spine-related presentations. OUTCOME MEASURES: Authorship by gender. METHODS: Retrospective bibliometric analysis with univariate and multivariate modeling to identify trends and predictors of gender diversity. RESULTS: Among 8,948 presentations, 750 (8.4%) had female first authors and 618 (6.9%) had female senior authors. There was no change in rates of female first authorship (p=.41) or senior authorship (p=.88) over time. The strongest predictors of female first authorship were having a female senior author (OR 7.32, p<.001), and delivering presentations at SRS (OR 1.95, p=.001). Factors negatively associated with female first authorship included poster format (OR 0.82, p=.039) and conference location in the United States/Canada (OR 0.76, p=.045). Similar trends were encountered for senior authorship. Productivity per senior author was similar between genders (p=.160); whereas a gender gap in productivity per first author during 2007 to 2011 (p=.020) equalized by 2017 to 2021 (p=.300). Among the 10 most productive authors of each gender, male authors delivered more presentations, but all authors shared similar format, content, and location. CONCLUSIONS: Women's representation in spine-related presentations did not increase at three major conferences over a 15-year period. Our findings regarding the positive effects of female mentorship, and international or virtual venues merit further investigation to address the gender gap. The upstream pipeline of recruiting women into academic spine surgery also needs to be addressed.

Human microglia maturation is underpinned by specific gene regulatory networks.

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Spontaneous chronic subdural haematoma due to hypoplastic rostral superior sagittal sinus.

The superior sagittal sinus (SSS) is a midline structure of the superficial cerebral venous system that drains the anterior cerebral hemispheres. Hypoplasia of the rostral SSS is a known variant, although associated complications are rare. A woman in her 30s presented for evaluation of a symptomatic left-sided acoustic neuroma and was found to have an incidental chronic subdural haematoma (SDH) over the left frontoparietal convexity without trauma or precipitating event. The SDH expanded on serial imaging and the patient eventually underwent left-sided frontoparietal craniotomy for haematoma evacuation. Haematological evaluation was benign, but angiography revealed absence of the anterior half of the SSS. We report the first case of spontaneous SDH in the setting of hypoplastic rostral SSS.

Shunt freedom in slit ventricle syndrome: using paradoxical ventriculomegaly following lumbar shunting to our advantage. Illustrative cases.

BACKGROUND: The authors present two cases of paradoxical ventriculomegaly after lumboperitoneal (LP) shunting in patients with slit ventricle syndrome (SVS). OBSERVATIONS: After placement of an LP shunt, both patients rapidly developed radiographic and clinically symptomatic ventricular enlargement. The then generous ventricular corridors allowed both patients to be treated by endoscopic third ventriculostomy (ETV) with concurrent removal of their LP shunt. The patients then underwent staged increases in their shunt resistance to the maximum setting and remain asymptomatic. LESSONS: The authors suggest that this paradoxical ventriculomegaly may have resulted from a pressure gradient between the shunt systems in the intra- and extraventricular spaces due to a noncommunicating etiology of their hydrocephalus. ETV may successfully exploit this newfound obstructive hydrocephalus and provide resolution of the radiographic and clinical hydrocephalus through allowing for improved communication between the cranial and lumbar cerebrospinal fluid spaces in SVS.

Towards a sustainable organic waste supply chain: A comparison of centralized and decentralized systems.

Proper disposal of Municipal Solid (MSW) waste is an important issue as it causes land, air, and water pollution. Organic MSW provides a habitat environment to insects and often it spreads dangerous diseases. Major reasons identified behind this as the non-separation of MSW at the source and lack of facilities (bins) in the appropriate place for collection of wastes. The present study has proposed an integrated three-stage model to provide a solution to the problem of (i) allocation of the bin for waste collection, (ii) allocation and comparison of centralized and decentralized composting plants, and finally, (iii) vehicle routing for waste collection. The proposed generic model is applied to an Indian city, Bilaspur located in the state of Chhattisgarh. From the results, it is observed that the first stage model provides an optimal number of bins required and allocation of it at minimum cost. Taking it as input for the second stage model, it identifies the best locations for centralized and decentralized composting plants. The result also reveals that decentralized composting plants are more economical than centralized plants. Finally, the third stage of the model identifies the vehicle routing for the waste collection considering both centralized and decentralized plants to minimize the cost. Further, sensitivity analysis is carried out on collection rate and participation percentage parameters to draw additional insights for better management of MSW.

Radiosurgery as a microsurgical adjunct: outcomes after microsurgical resection of intracranial arteriovenous malformations previously treated with stereotactic radiosurgery.

OBJECTIVE: Microsurgical resection of arteriovenous malformations (AVMs) can be aided by staged treatment consisting of stereotactic radiosurgery followed by resection in a delayed fashion. This approach is particularly useful for high Spetzler-Martin (SM) grade lesions because radiosurgery can reduce flow through the AVM, downgrade the SM rating, and induce histopathological changes that additively render the AVM more manageable for resection. The authors present their 28-year experience in managing AVMs with adjunctive radiosurgery followed by resection. METHODS: The authors retrospectively reviewed records of patients treated for cerebral AVMs at their institution between January 1990 and August 2019. All patients who underwent stereotactic radiosurgery (with or without embolization), followed by resection, were included in the study. Of 1245 patients, 95 met the eligibility criteria. Univariate and multivariate regression analyses were performed to assess relationships between key variables and clinical outcomes. RESULTS: The majority of lesions treated (53.9%) were high grade (SM grade IV-V), 31.5% were intermediate (SM grade III), and 16.6% were low grade (SM grade I-II). Hemorrhage was the initial presenting sign in half of all patients (49.5%). Complete resection was achieved among 84% of patients, whereas 16% had partial resection, the majority of whom received additional radiosurgery. Modified Rankin Scale (mRS) scores of 0-2 were achieved in 79.8% of patients, and 20.2% had poor (mRS scores 3-6) outcomes. Improved (44.8%) or stable (19%) mRS scores were observed among 63.8% of patients, whereas 36.2% had a decline in mRS scores. This includes 22 patients (23.4%) with AVM hemorrhage and 6 deaths (6.7%) outside the perioperative period but prior to AVM obliteration. CONCLUSIONS: Stereotactic radiosurgery is a useful adjunct in the presurgical management of cerebral AVMs. Multimodal therapy allowed for high rates of AVM obliteration and acceptable morbidity rates, despite the predominance of high-grade lesions in this series of patients.

Results of three or more Gamma Knife radiosurgery procedures for recurrent trigeminal neuralgia.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is an established surgical option for the treatment of trigeminal neuralgia (TN), particularly for high-risk surgical candidates and those with recurrent pain. However, outcomes after three or more GKRS treatments have rarely been reported. Herein, the authors reviewed outcomes among patients who had undergone three or more GKRS procedures for recurrent TN. METHODS: The authors conducted a multicenter retrospective analysis of patients who had undergone at least three GKRS treatments for TN between July 1997 and April 2019 at two different institutions. Clinical characteristics, radiosurgical dosimetry and technique, pain outcomes, and complications were reviewed. Pain outcomes were scored on the Barrow Neurological Institute (BNI) scale, including time to pain relief (BNI score ≤ III) and recurrence (BNI score > III). RESULTS: A total of 30 patients were identified, including 16 women and 14 men. Median pain duration prior to the first GKRS treatment was 10 years. Three patients (10%) had multiple sclerosis. Time to pain relief was longer after the third treatment (p = 0.0003), whereas time to pain recurrence was similar across each of the successive treatments (p = 0.842). Complete or partial pain relief was achieved in 93.1% of patients after the third treatment. The maximum pain relief achieved after the third treatment was significantly better among patients with no prior percutaneous procedures (p = 0.0111) and patients with shorter durations of pain before initiation of GKRS therapy (p = 0.0449). New or progressive facial sensory dysfunction occurred in 29% of patients after the third GKRS treatment and was reported as bothersome in 14%. One patient developed facial twitching, while another experienced persistent lacrimation. No statistically significant predictors of adverse effects following the third treatment were found. Over a median of 39 months of follow-up, 77% of patients maintained complete or partial pain relief. Three patients underwent a fourth GKRS treatment, including one who ultimately received five treatments; all of them reported sustained pain relief at the extended follow-up. CONCLUSIONS: The authors describe the largest series to date of patients undergoing three or more GKRS treatments for refractory TN. A third treatment may produce outcomes similar to those of the first two treatments in terms of long-term pain relief, recurrence, and adverse effects.

Minimally Invasive L5-S1 Oblique Lumbar Interbody Fusion With Simultaneous Robotic Single Position Posterior Fixation: 2-Dimensional Operative Video.

The unique anatomy at L5-S1 presents different challenges and considerations to be made when compared to other areas in the lumbar spine. In this way, the oblique lumbar interbody fusion (OLIF) is more closely related to a supine anterior lumbar interbody fusion (ALIF) except that the former is performed in a lateral position down a smaller minimally invasive retroperitoneal corridor. This lateral positioning at L5-S1, however, provides an opportunity for single-position surgery simultaneously with posterior fixation, which is not afforded by other approaches. We present here a case of a 57-yr-old male with a prior right-sided L5-S1 microdiscectomy who presents with worsening lumbar radiculopathy and foot drop. He subsequently underwent a minimally invasive L5-S1 OLIF with posterior instrumentation placed bilaterally while remaining in a single lateral position (Mazor X Stealth Edition, Medtronic, Dublin, Ireland). Both the anterior OLIF surgeon and posterior instrumentation surgeon were able to work simultaneously. There is currently a need for further high-quality operative videos showing the L5-S1 OLIF technique, and to our knowledge, this is the first video demonstrating a 2-surgeon near-simultaneous workflow approach using a spinal robotics platform at this level. There is no identifying information in this video. A patient consent was obtained for the surgical procedure and for publishing of the material included in the video.

Traumatic ischemic injury in a top of the basilar distribution: a case report.

BACKGROUND: Top of the basilar syndrome is a rare, heterogeneous disorder that has previously only been described in the setting of acute ischemic stroke in predominantly elderly patients. We present the first reported case of traumatic brain injury (TBI) causing ischemia in a top of the basilar distribution. CASE PRESENTATION: A 19-year-old woman suffered an acute subdural hematoma and sustained hypoxemia after being struck by a motor vehicle. Neurosurgical evacuation of the hematoma was undertaken. Magnetic resonance imaging revealed ischemic injury in the midbrain and diencephalic structures fitting a top of the basilar distribution. No associated vascular injury was identified. The patient was eventually discharged in a state of persistent unresponsive wakefulness. CONCLUSIONS: Ischemia in a top of the basilar distribution may occur in the setting of TBI. A high degree of clinical suspicion is required to identify this disorder. Further study of the complex inflammatory microenvironment and associated tissue perfusion dynamics in TBI are needed in order to elucidate the mechanisms underlying ischemic injury patterns, develop management paradigms and predict prognosis.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

The Significance of Nonlinear Screening and the pH Interference Mechanism in Field-Effect Transistor Molecular Sensors.

Electrolyte screening is well known for its detrimental impact on the sensitivity of liquid-gated field-effect transistor (FET) molecular sensors and is mostly described by the linearized Debye-Hückel model. However, charged and pH-sensitive FET sensing surfaces can limit the FET molecular sensitivity beyond the Debye-Hückel screening formalism. Pre-existing surface charges can lead to the breakdown of Debye-Hückel screening and induce enhanced nonlinear Poisson-Boltzmann screening. Moreover, the charging of the pH-sensitive surface groups interferes with biomolecule sensing resulting in a pH interference mechanism. With analytical equations and TCAD simulations, we highlight that the Debye-Hückel approximation can underestimate screening and overestimate FET molecular sensitivity by more than an order of magnitude. Screening strengthens significantly beyond Debye-Hückel in the proximity of even moderately charged surfaces and biomolecule charge densities (≥1 × 1012 q/cm2). We experimentally show the strong impact of both nonlinear screening and the pH interference effect on charge-based biomolecular sensing using a model system based on the covalent binding of single-stranded DNA on silicon FET sensors. The DNA signal increases from 24 mV at pH 7 to 96 mV at pH 3 in 1.5 mM PBS for a DNA density of 7 × 1012 DNA/cm2. Our model quantitatively explains the signal's pH dependence with roughly equal nonlinear screening and pH interference contributions. This work shows the importance of reducing the net charge and the pH sensitivity of the sensing surface to improve molecular sensing. Therefore, tailoring the gate dielectric and functional layer of FET sensors is a promising route to strong silicon FET molecular sensitivity boosts.

Rotation flap distraction osteogenesis for unicoronal synostosis.

Unicoronal craniosynostosis is notoriously difficult to treat, with long-term studies demonstrating high rates of relapse and the need for reoperation using open fronto-orbital advancement. Applying the principles of distraction osteogenesis to cranial vault remodeling has demonstrated promising short-term results that compare favorably with traditional methods, with simultaneous correction of both frontofacial and endocranial morphology, along with significant increases in intracranial volume. Here, the authors demonstrate their technique for rotation flap distraction osteogenesis in the treatment of unicoronal synostosis and provide case examples. The video can be found here: https://vimeo.com/519505008.

Predicting Functional Outcomes and Length of Stay Following Acoustic Neuroma Resection.

OBJECTIVES: To examine whether simple mobility assessments can predict functional limitations and length of hospitalization after acoustic neuroma (AN) resection. STUDY DESIGN: Prospective case series. METHODS: A prospective clinical study of adult patients undergoing AN resection by either the translabyrinthine, retrosigmoid, or middle fossa approach was conducted at a tertiary center. Preoperative mobility assessments included the functional gait assessment (FGA) and the 10-m walk (10 MW). Postoperatively, the Activity Measure for Post-Acute Care (AMPAC, at 48 hours), FGA, and 10 MW (at 1 week) were obtained. Demographic and medical data were collected. RESULTS: One hundred and thirty-eight patients were analyzed (mean age: 48.3 years, 68.8% female). Mean length of stay (LOS) was 3.1 days. The translabyrinthine approach was most commonly performed (48.6%). On regression analyses, preoperative FGA (P = 0.03) and 48-hour postoperative AM-PAC (P < 0.001) independently predicted LOS, even after accounting for age, gender, body mass index, and tumor size. On receiver operating characteristic analysis, a preoperative FGA cut score of 25.5 predicted a protracted hospital stay (>4 days) with a sensitivity of 77% and specificity of 50% (area under curve: 68.5). CONCLUSION: This study demonstrated that preoperative mobility assessments can predict functional limitations and LOS after AN resection. These objective tools can be used by clinicians to manage expectations and guide preoperative counseling in patients considering surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:644-648, 2021.

Heme Causes Pain in Sickle Mice via Toll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation.

Aims: Lifelong pain is a hallmark feature of sickle cell disease (SCD). How sickle pathobiology evokes pain remains unknown. We hypothesize that increased cell-free heme due to ongoing hemolysis activates toll-like receptor 4 (TLR4), leading to the formation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Together, these processes lead to spinal microglial activation and neuroinflammation, culminating in acute and chronic pain. Results: Spinal heme levels, TLR4 transcripts, oxidative stress, and ER stress were significantly higher in sickle mice than controls. In vitro, TLR4 inhibition in spinal cord microglial cells attenuated heme-induced ROS and ER stress. Heme treatment led to a time-dependent increase in the characteristic features of sickle pain (mechanical and thermal hyperalgesia) in both sickle and control mice; this effect was absent in TLR4-knockout sickle and control mice. TLR4 deletion in sickle mice attenuated chronic and hypoxia/reoxygenation (H/R)-evoked acute hyperalgesia. Sickle mice treated with the TLR4 inhibitor resatorvid; selective small-molecule inhibitor of TLR4 (TAK242) had significantly reduced chronic hyperalgesia and had less severe H/R-evoked acute pain with quicker recovery. Notably, reducing ER stress with salubrinal ameliorated chronic hyperalgesia in sickle mice. Innovation: Our findings demonstrate the causal role of free heme in the genesis of acute and chronic sickle pain and suggest that TLR4 and/or ER stress are novel therapeutic targets for treating pain in SCD. Conclusion: Heme-induced microglial activation via TLR4 in the central nervous system contributes to the initiation and maintenance of sickle pain via ER stress in SCD. Antioxid. Redox Signal. 34, 279-293.