Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.

The Use of Psychedelics in the Treatment of Medical Conditions: An Analysis of Currently Registered Psychedelics Studies in the American Drug Trial Registry.

Although early therapeutic research on psychedelics dates back to the 1940s, this field of investigation was met with many cultural and legal challenges in the 1970s. Over the past two decades, clinical trials using psychedelics have resumed. Therefore, the goal of this study was to (1) better characterize the recent uptrend in psychedelics in clinical trials and (2) identify areas where potentially new clinical trials could be initiated to help in the treatment of widely prevalent medical disorders. A systematic search was conducted on the clinicaltrials.gov database for all registered clinical trials examining the use of psychedelic drugs and was both qualitatively and quantitatively assessed. Analysis of recent studies registered in clinicaltrials.gov was performed using Pearson's correlation coefficient testing. Statistical analysis and visualization were performed using R software. In totality, 105 clinical trials met this study's inclusion criteria. The recent uptrend in registered clinical trials studying psychedelics (p = 0.002) was similar to the uptrend in total registered clinical trials in the registry (p < 0.001). All trials took place from 2007 to 2020, with 77.1% of studies starting in 2017 or later. A majority of clinical trials were in phase 1 (53.3%) or phase 2 (25.7%). Common disorders treated include substance addiction, post-traumatic stress disorder, and major depressive disorder. Potential research gaps include studying psychedelics as a potential option for symptomatic treatment during opioid tapering. There appears to be a recent uptrend in registered clinical trials studying psychedelics, which is similar to the recent increase in overall trials registered. Potentially, more studies could be performed to evaluate the potential of psychedelics for symptomatic treatment during opioid tapering and depression refractory to selective serotonin reuptake inhibitors.

Cost analysis comparison between anterior and posterior cervical spine approaches.

Background: The costs of cervical spine surgery have steadily increased. We performed a 5-year propensity scoring-matched analysis of 276 patients undergoing anterior versus posterior cervical surgery at one institution. Methods: We performed propensity score matching on financial data from 276 patients undergoing 1-3 level anterior versus posterior cervical fusions for degenerative disease (2015-2019). Results: We found no significant difference between anterior versus posterior approaches for hospital costs ($42,529.63 vs. $45,110.52), net revenue ($40,877.25 vs. $34,036.01), or contribution margins ($14,230.19 vs. $6,312.54). Multivariate regression analysis showed variables significantly associated with the lower contribution margins included age (ß = -392.3) and length of stay (LOS; ß = -1151). Removing age/LOS from the analysis, contribution margins were significantly higher for the anterior versus posterior approach ($17,824.16 vs. $6,312.54, P = 0.01). Conclusion: Anterior cervical surgery produced higher contribution margins compared to posterior approaches, most likely because posterior surgery was typically performed in older patients requiring longer LOS.

Evaluating the incidence and predictors of anti-NMDAR encephalitis in a contemporary cohort of patients diagnosed with dermoid tumors: A national inpatient sample analysis.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a form of encephalitis previously associated with dermoid tumors. However, most studies in the literature evaluating the disease are case reports and small patient cohorts, limiting robust statistical analysis. Here, we demonstrate predictors of anti-NMDAR encephalitis in a large cohort of US patients. METHODS: We used the 2016 National Inpatient Sample (NIS) to identify a cohort of 24,270 admitted for an ovarian dermoid tumor. Of these patients, 50 (0.21%) were diagnosed with anti-NMDAR encephalitis. Patient demographics, hospital characteristics, length of stay (LOS), and complications were collected. Statistical analysis consisted of odds ratios with chi-square testing to compare categorical variables. RESULTS: The mean age of all patients with dermoid tumors was 45.5 ± 18.0 years, and the mean age of patients with diagnosed anti-NMDAR encephalitis was 27.4 ± 4.9 years. The mean LOS in the dermoid tumor cohort was 3.5 ± 4.9 days, while the mean LOS in the anti-NMDAR encephalitis cohort was 31.9 ± 25.9 days (p < 0.001). The mean cost in the dermoid tumor cohort was $44,813.18±$54,305.90, while the mean cost in the anti-NMDAR encephalitis cohort was $445,628.60±$665,423.40 (p < 0.001). Patients with age above 30 years with dermoid tumors had significantly lower odds of developing anti-NMDAR encephalitis compared to patients younger than 30 years (OR: 0.19; 95%CI: 0.045-0.67; p-value: 0.003). White patients had significantly lower odds of developing anti-NMDAR encephalitis (OR: 0.19; 95%CI: 0.026-0.77; p-value: 0.013), and Black patients had significantly higher odds of developing anti-NMDAR encephalitis (OR: 3.45; 95%CI: 1.00-12.46; p-value: 0.044). CONCLUSION: Patient predictors of developing anti-NMDAR encephalitis include age, race, ethnicity and patients who go on to develop anti-NMDAR encephalitis have a significantly increased hospital LOS and cost compared to those who do not. Future research, including multi-center clinical trials and longitudinal data, is necessary to fully cement the findings of this manuscript.

Successful use of stereotactic navigation in posterior spinal fusion T10-S2 with bilateral iliac screw fixation in a patient with prior spinal surgeries and osteoporosis: A case report.

INTRODUCTION AND IMPORTANCE: Degenerative lumbar scoliosis is a prominent cause of adult spinal deformity with an increasing prevalence as the population ages. This pathology is associated with debilitating symptoms, including radicular back pain and lower extremity claudication. Surgical realignment of the spine and restoration of sagittal imbalance can reduce low back pain. Chronic sacroiliac dysfunction commonly causes low back radicular pain. We present a complicated case where stereotactic navigation facilitated an extensive fusion and decompression procedure for adult spinal deformity in an obese patient with multiple prior surgeries for scoliosis and sacroiliac joint pathology. CASE PRESENTATION: A 69-year-old, obese female with scoliosis refractory to multiple interventions presented with severe, radicular lower back pain. On examination of the right lower extremity (RLE), she had mild weakness (3/5 strength) and reduced sensation to light touch over its anterolateral aspect (dermatome L4). She was unable to perform single leg stance or tandem walk. Imaging revealed moderate mid-lumbar levoscoliosis, severe degenerative disc disease and facet hypertrophy changes in the setting of prior multilevel lumbar fusion, and consecutive nerve root impingement between L1 and L5 (worst at L3-4). DEXA scan was consistent with osteoporosis. The patient underwent lumbar laminectomy with posterior fusion of T10-ilium, transforaminal lumbar interbody fusion, osteotomy, and decompression using stereotactic navigation. The presence of SI titanium dowels from her previous SI fusion procedure posed a challenge with respect to achieving pelvic fixation. CLINICAL DISCUSSION: Iliac screw placement is a critical adjunctive to lumbosacral fusion, notably for prevention of pseudoarthrosis; however, patients with prior SI fusion may present a biomechanical challenge to surgeons due to obstruction of the surgical site. The O-arm neuronavigation system was successfully used to bypass this obstruction and provide sacroiliac fixation in this procedure. CONCLUSION: Stereotactic navigation (The O-arm Surgical Imaging System) can effectively be used to circumvent prior SI fusion in osteoporotic bone.

The minimally conscious state: an analysis of current clinical trials registered in ClinicalTrials.gov.

The minimally conscious state (MCS) is a disorder of consciousness described in recent years for patients who have behavioral responses to stimuli that do not meet the classification of chronic vegetative state (CVS) or coma. This distinction is valuable in clinical practice, as minimally conscious patients may require different treatments and may have different long-term outcomes when compared to vegetative states or coma. In this report, we analyzed the ClinicalTrials.gov database to systematically assess all clinical trials regarding MCS. The database was queried using the term "minimally conscious state" in the "condition or disease" search parameter. Of the studies identified, those that had suspended, terminated, or otherwise unknown statuses were excluded. In total, 41 studies were analyzed. The included studies were initiated between 2008 and 2020, with the majority (63%) beginning in 2015 or later. Of the primary intervention modalities included, 15 (37%) evaluated stimulation modalities such as transcranial magnetic stimulation, transcranial direct current stimulation, implantable neurostimulation, vagus nerve stimulation, focused ultrasound and median nerve stimulation. Additionally, 5 (12%) used some form of behavioral therapy. A total of 4 (10%) studies involved pharmaceutical intervention, including dopamine agonists, analgesics and sedatives. Finally, 4 (10%) studies sought to determine the validity of current diagnostic methods and systems used to assess the status of patients in MCSs. Since the definition and criteria for CVS and MCS have been established, these two conditions remain closely associated despite evidence of different patient outcomes and treatment options. Many clinical trials are underway assessing interventions with stimulation. However, the trials are lacking with respect to diagnostic methods and pharmaceutical treatment.