Karen Elizabeth Malacon

All Publications

• Trends in Management of Osteoporosis Following Primary Vertebral Compression Fracture. Journal of the Endocrine Society Malacon, K., Beach, I., Touponse, G., Rangwalla, T., Lee, J., Zygourakis, C. 2023; 7 (7): bvad085

  Abstract

  Osteoporosis affects more than 200 million individuals worldwide and predisposes to vertebral compression fractures (VCFs). Given undertreatment of fragility fractures, including VCFs, we investigate current anti-osteoporotic medication prescribing trends.Patients 50 and older with a diagnosis of primary closed thoracolumbar VCF between 2004 and 2019 were identified from the Clinformatics® Data Mart database. Multivariate analysis was performed for demographic and clinical treatment and outcome variables.Of 143 081 patients with primary VCFs, 16 780 (11.7%) were started on anti-osteoporotic medication within a year; 126 301 (88.3%) patients were not started on medication. The medication cohort was older (75.4 ± 9.3 vs 74.0 ± 12.3 years, P < .001), had higher Elixhauser Comorbidity Index scores (4.7 ± 6.2 vs 4.3 ± 6.7, P < .001), was more likely to be female (81.1% vs 64.4%, P < .001), and was more likely to have a formal osteoporosis diagnosis (47.8% vs 32.9%) than the group that did not receive medication. Alendronate (63.4%) and calcitonin (27.8%) were the most commonly initiated medications. The proportion of individuals receiving anti-osteoporotic medication within the year following VCF peaked in 2008 (15.2%), then declined until 2012 with a modest increase afterward.Osteoporosis remains undertreated after low-energy VCFs. New anti-osteoporotic medication classes have been approved in recent years. Bisphosphonates remain the most prescribed class. Increasing recognition and treatment of osteoporosis is paramount to decreasing the risk of subsequent fractures.

  View details for DOI 10.1210/jendso/bvad085

  View details for PubMedID 37388575

  View details for PubMedCentralID PMC10306270

• Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system. Molecular psychiatry Smith, C. J., Rendina, D. N., Kingsbury, M. A., Malacon, K. E., Nguyen, D. M., Tran, J. J., Devlin, B. A., Raju, R. M., Clark, M. J., Burgett, L., Zhang, J. H., Cetinbas, M., Sadreyev, R. I., Chen, K., Iyer, M. S., Bilbo, S. D. 2023

  Abstract

  Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

  View details for DOI 10.1038/s41380-023-02108-w

  View details for PubMedID 37198262

• Trends, Payments, and Costs Associated with BMP Use in Medicare Beneficiaries Undergoing Spinal Fusion. The spine journal : official journal of the North American Spine Society Wadhwa, H., Wu, J. Y., Malacon, K., Ames, C., Ratliff, J., Zygourakis, C. 2023

  Abstract

  Bone morphogenic protein (BMP) promotes bony fusion but increases costs. Recent trends in BMP use among Medicare patients have not been well-characterized.To assess utilization trends, complication, payments, and costs associated with BMP use in spinal fusion in a Medicare-insured population.Retrospective cohort study PATIENT SAMPLE: : 316,070 patients who underwent spinal fusion in a 20% sample of Medicare-insured patients, 2006-2015 OUTCOME MEASURES: : Utilization trends across time and geography, complications, payments, and costs.Patients were stratified by fusion type and diagnosis. Multivariable logistic and linear regression were used to adjust for the effect of baseline characteristics on complications and total payments or cost, respectively.BMP was used in 60,249 cases (19.1%). BMP utilization rates decreased from 23.1% in 2006 to 12.0% in 2015, most significantly in anterior cervical (7.5% to 3.1%), posterior cervical (17.0% to 8.3%), and posterior lumbar fusions (31.5% to 15.8%). There are significant state- and region-level geographic differences in BMP utilization. Across all years, states with the highest BMP use were Indiana (28.5%), Colorado (26.6%), and Nevada (25.7%). States with the lowest BMP use were Maine (2.3%), Vermont (8.2%), and Mississippi (10.4%). After multivariate risk adjustment, BMP use was associated with decreased overall complications in thoracic (OR (95% CI): 0.89 (0.81-0.99) and anterior lumbar fusions (OR (95% CI): 0.89 (0.84-0.95)), as well as increased reoperation rates in anterior cervical (OR (95% CI): 1.11 (1.04-1.19)), posterior cervical (OR (95% CI): 1.14 (1.04-1.25)), thoracic (OR (95% CI): 1.32 (1.23-1.41)), and posterior lumbar fusions (OR (95% CI): 1.11 (1.06-1.16)). BMP use was also associated with greater total costs, independent of fusion type, after multivariate risk adjustment (p < 0.0001). Payments, however, were comparable between groups in anterior and posterior cervical fusion with or without BMP. BMP use was associated with greater total payments in thoracic, anterior lumbar, and posterior lumbar fusions. Notably, the difference in payments was smaller than the associated cost increase in all fusion types.BMP use has declined across all fusion types over the last decade, after a peak in 2007. While BMP is associated with greater costs, reimbursement does not increase proportionally with BMP cost.

  View details for DOI 10.1016/j.spinee.2023.01.012

  View details for PubMedID 36709918

• First reported use of machine vision image guided system for unstable thoracolumbar fusion: Technical case report INTERDISCIPLINARY NEUROSURGERY-ADVANCED TECHNIQUES AND CASE MANAGEMENT Malacon, K., Fatemi, P., Zygourakis, C. C. 2022; 30

  View details for DOI 10.1016/j.inat.2022.101641

  View details for Web of Science ID 000844034400007

• Operative Versus Nonoperative Management of Unstable Spine Fractures in the Elderly: Outcomes and Mortality. Spine Malacon, K., Rangwalla, T., Wadhwa, H., Zygourakis, C. 2022

  Abstract

  STUDY DESIGN: Retrospective cohort study.OBJECTIVE: To assess outcomes and mortality in elderly patients following unstable spine fractures depending on treatment modality.SUMMARY OF BACKGROUND DATA: Operative management of unstable spine fractures in the elderly remains controversial due to increased risk of perioperative complications. Mortality rates after operative versus nonoperative treatment of these injuries have not been well-characterized.METHODS: Patients age >65 with unstable spine fractures without neurologic injury from 2015-2021 were identified from the Clinformatics Data Mart (CDM) Database. Demographics, complications, and mortality were collected. Multivariable logistic regression was used to adjust for the effect of baseline characteristics on mortality following unstable fracture diagnosis.RESULTS: Of 3,688 patients included, 1,330 (36.1%) underwent operative management and 2,358 (63.9%) nonoperative. At baseline, nonoperative patients were older, female, had higher Elixhauser comorbidity scores, and were more likely to have a cervical fracture. Operative patients had a longer length of stay in the hospital compared to nonoperative patients (9.7 vs. 7.7d; P<0.001). Although patients in the operative group had higher rates of readmission at 30-, 60-, 90-, and 120-days after diagnosis (P<0.01), they had lower mortality rates up to 5 years after injury. After adjusting for covariates, nonoperative patients had a 60% greater risk of mortality compared to operative patients (HR: 1.60 [1.40-1.78], P<0.001). After propensity score matching, operative patients age 65-85 had greater survivorship compared to their nonoperative counterparts.CONCLUSION: Elderly patients with an unstable spine fracture who undergo surgery experience lower mortality rates up to five years post diagnosis compared to patients who received nonoperative management, despite higher hospital readmission rates and an overall perioperative complication rate of 37.3%. Operating on elderly patients with unstable spine fractures may outweigh the risks and should be considered as a viable treatment option in appropriately selected patients.

  View details for DOI 10.1097/BRS.0000000000004466

  View details for PubMedID 36083602

• Prenatal opioid exposure inhibits microglial sculpting of the dopamine system selectively in adolescent male offspring. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Smith, C. J., Lintz, T., Clark, M. J., Malacon, K. E., Abiad, A., Constantino, N. J., Kim, V. J., Jo, Y. C., Alonso-Caraballo, Y., Bilbo, S. D., Chartoff, E. H. 2022; 47 (10): 1755-1763

  Abstract

  The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.

  View details for DOI 10.1038/s41386-022-01376-4

  View details for PubMedID 35835992

  View details for PubMedCentralID PMC9372181

• Prenatal environmental stressors impair postnatal microglia function and adult behavior in males. Cell reports Block, C. L., Eroglu, O., Mague, S. D., Smith, C. J., Ceasrine, A. M., Sriworarat, C., Blount, C., Beben, K. A., Malacon, K. E., Ndubuizu, N., Talbot, A., Gallagher, N. M., Chan Jo, Y., Nyangacha, T., Carlson, D. E., Dzirasa, K., Eroglu, C., Bilbo, S. D. 2022; 40 (5): 111161

  Abstract

  Gestational exposure to environmental toxins and socioeconomic stressors is epidemiologically linked to neurodevelopmental disorders with strong male bias, such as autism. We model these prenatal risk factors in mice by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly activates the maternal immune system. Only male offspring display long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions. Cellularly, prenatal stressors diminish microglial function within the anterior cingulate cortex, a central node of the social coding network, in males during early postnatal development. Precise inhibition of microglial phagocytosis within the anterior cingulate cortex (ACC) of wild-type (WT) mice during the same critical period mimics the impact of prenatal stressors on a male-specific behavior, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development.

  View details for DOI 10.1016/j.celrep.2022.111161

  View details for PubMedID 35926455

• Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M. H., Wood, J., O'Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., Mancusi, R., Yalçın, B., Taylor, K. R., Acosta-Alvarez, L., Malacon, K., Keough, M. B., Ni, L., Woo, P. J., Contreras-Esquivel, D., Toland, A. M., Gehlhausen, J. R., Klein, J., Takahashi, T., Silva, J., Israelow, B., Lucas, C., Mao, T., Peña-Hernández, M. A., Tabachnikova, A., Homer, R. J., Tabacof, L., Tosto-Mancuso, J., Breyman, E., Kontorovich, A., McCarthy, D., Quezado, M., Vogel, H., Hefti, M. M., Perl, D. P., Liddelow, S., Folkerth, R., Putrino, D., Nath, A., Iwasaki, A., Monje, M. 2022

  Abstract

  COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

  View details for DOI 10.1016/j.cell.2022.06.008

  View details for PubMedID 35768006

• First reported use of real-time intraoperative computed tomography angiography image registration using the Machine-vision Image Guided Surgery system: illustrative case. Journal of neurosurgery. Case lessons Wadhwa, H., Malacon, K., Medress, Z. A., Leung, C., Sklar, M., Zygourakis, C. C. 2021; 1 (18): CASE2125

  Abstract

  Vertebral artery injury is a devastating potential complication of C1-2 posterior fusion. Intraoperative navigation can reduce the risk of neurovascular complications and improve screw placement accuracy. However, the use of intraoperative computed tomography (CT) increases radiation exposure and operative time, and it is unable to image vascular structures. The Machine-vision Image Guided Surgery (MvIGS) system uses optical topographic imaging and machine vision software to rapidly register using preoperative imaging. The authors presented the first report of intraoperative navigation with MvIGS registered using a preoperative CT angiogram (CTA) during C1-2 posterior fusion.MvIGS can register in seconds, minimizing operative time with no additional radiation exposure. Furthermore, surgeons can better adjust for abnormal vertebral artery anatomy and increase procedure safety.CTA-guided navigation generated a three-dimensional reconstruction of cervical spine anatomy that assisted surgeons during the procedure. Although further study is needed, the use of intraoperative MvIGS may reduce the risk of vertebral artery injury during C1-2 posterior fusion.

  View details for DOI 10.3171/CASE2125

  View details for PubMedID 35855470

  View details for PubMedCentralID PMC9245760

• Internal state configures olfactory behavior and early sensory processing in Drosophila larvae SCIENCE ADVANCES Vogt, K., Zimmerman, D. M., Schlichting, M., Hernandez-Nunez, L., Qin, S., Malacon, K., Rosbash, M., Pehlevan, C., Cardona, A., Samuel, A. T. 2021; 7 (1)

  View details for DOI 10.1126/sciadv.abd6900

  View details for Web of Science ID 000605159200029

• First reported use of real-time intraoperative computed tomography angiography image registration using the Machine-vision Image Guided Surgery system: illustrative case Journal of Neurosurgery: Case Lessons Wadhwa, H., Malacon, K., Medress, Z. A., Leung, C., Sklar, M., Zygourakis, C. C. 2021

  View details for DOI 10.3171/CASE2125

• Sex differences in microglia as a risk factor for Alzheimer's disease Sex and Gender Differences in Alzheimer's disease Delage , C., Rendina , D. N., Malacon , K. E., Tremblay , M., Bilbo , S. D. Elsevier Inc.. 2021; 1: 79-104
• Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number BRAIN BEHAVIOR AND IMMUNITY Smith, C. J., Kingsbury, M. A., Dziabis, J. E., Hanamsagar, R., Malacon, K. E., Tran, J. N., Norris, H. A., Gulino, M., Bordt, E. A., Bilbo, S. D. 2020; 90: 332–45

  Abstract

  Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling.

  View details for DOI 10.1016/j.bbi.2020.08.013

  View details for Web of Science ID 000577976900031

  View details for PubMedID 32860938

  View details for PubMedCentralID PMC7556772