Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Procedural volume is linearly associated with mortality, major complications, and readmissions in patients undergoing malignant brain tumor resection.

PURPOSE: Improved outcomes have been noted in patients undergoing malignant brain tumor resection at high-volume centers. Studies have arbitrarily chosen high-volume dichotomous cutoffs and have not evaluated volume-outcome associations at specific institutional procedural volumes. We sought to establish the continuous association of volume with patient outcomes and identify cutoffs significantly associated with mortality, major complications, and readmissions. We hypothesized that a linear volume-outcome relationship can estimate likelihood of adverse outcomes when comparing any two volumes. METHODS: The patient cohort was identified with ICD-10 coding in the Nationwide Readmissions Database(NRD). The association of volume and mortality, major complications, and 30-/90-day readmissions were evaluated in multivariate analyses. Volume was used as a continuous variable with two/three-piece splines, with various knot positions to reflect the best model performance, based on the Quasi Information Criterion(QIC). RESULTS: From 2016 to 2018, 34,486 patients with malignant brain tumors underwent resection. When volume was analyzed as a continuous variable, mortality risk decreased at a steady rate of OR 0.988 per each additional procedure increase for hospitals with 1-65 cases/year(95% CI 0.982-0.993, p < 0.0001). Risk of major complications decreased from 1 to 41 cases/year(OR 0.983, 95% CI 0.979-0.988, p < 0.0001), 30-day readmissions from 1 to 24 cases/year(OR 0.987, 95% CI 0.979-0.995, p = 0.001) and 90-day readmissions from 1 to 23 cases/year(OR 0.989, 95% CI 0.983-0.995, p = 0.0003) and 24-349 cases/year(OR 0.9994, 95% CI 0.999-1, p = 0.01). CONCLUSION: In multivariate analyses, institutional procedural volume remains linearly associated with mortality, major complications, and 30-/90-day readmission up to specific cutoffs. The resulting linear association can be used to calculate relative likelihood of adverse outcomes between any two volumes.

Flavonoid quercetin and its glucuronide and sulfate conjugates bind to 67-kDa laminin receptor and prevent neuronal cell death induced by serum starvation.

Quercetin, a dietary flavonoid, has been shown to protect against various neurodegenerative diseases with mechanisms largely unknown. After oral administration, quercetin is rapidly conjugated, and the aglycone is not detectable in the plasma and brain. However, its glucuronide and sulfate conjugates are present only at low nanomolar concentrations in the brain. Since quercetin and its conjugates have limited antioxidant capability at low nanomolar concentrations, it is crucial to determine whether they induce neuroprotection by binding to high-affinity receptors. Previously we found that (-)-epigallocatechin-3-gallate (EGCG), a polyphenol from green tea, induces neuroprotection by binding to the 67-kDa laminin receptor (67LR). Therefore, in this study, we determined whether quercetin and its conjugates bind 67LR to induce neuroprotection and compared their ability with EGCG. Based on the quenching of intrinsic tryptophan fluorescence of peptide G (residues 161-180 in 67LR), we found quercetin, quercetin-3-O-glucuronide, and quercetin-3-O-sulfate bind to this peptide with a high affinity comparable to EGCG. Molecular docking using the crystal structure of 37-kDa laminin receptor precursor supported the high-affinity binding of all these ligands to the site corresponding to peptide G. A pretreatment with quercetin (1-1000 nM) did not effectively protect Neuroscreen-1 cells from death induced by serum starvation. Contrarily, a pretreatment with low concentrations (1-10 nM) of quercetin conjugates better protected these cells than quercetin and EGCG. The 67LR-blocking antibody substantially prevented neuroprotection by all these agents, suggesting the role of 67LR in this process. Collectively, these studies reveal that quercetin induces neuroprotection primarily through its conjugates via high affinity binding to 67LR.

Particulate matter exposure and chronic cerebral hypoperfusion promote oxidative stress and induce neuronal and oligodendrocyte apoptosis in male mice.

Chronic cerebral hypoperfusion (CCH) may amplify the neurotoxicity of nanoscale particulate matter (nPM), resulting in white matter injury. This study characterized the joint effects of nPM (diameter ≤ 200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) exposure on neuronal and white matter injury in a murine model. nPM was collected near a highway and re-aerosolized for exposure. Ten-week-old C57BL/6 male mice were randomized into four groups: filtered air (FA), nPM, FA + BCAS, and nPM + BCAS. Mice were exposed to FA or nPM for 10 weeks. BCAS surgeries were performed. Markers of inflammation, oxidative stress, and apoptosis were examined. nPM + BCAS exposure increased brain hemisphere TNFα protein compared to FA. iNOS and HNE immunofluorescence were increased in the corpus callosum and cerebral cortex of nPM + BCAS mice compared to FA. While nPM exposure alone did not decrease cortical neuronal cell count, nPM decreased corpus callosum oligodendrocyte cell count. nPM exposure decreased mature oligodendrocyte cell count and increased oligodendrocyte precursor cell count in the corpus callosum. nPM + BCAS mice exhibited a 200% increase in cortical neuronal TUNEL staining and a 700% increase in corpus callosum oligodendrocyte TUNEL staining compared to FA. There was a supra-additive interaction between nPM and BCAS on cortical neuronal TUNEL staining (2.6× the additive effects of nPM + BCAS). nPM + BCAS exposure increased apoptosis, neuroinflammation, and oxidative stress in the cerebral cortex and corpus callosum. nPM + BCAS exposure increased neuronal apoptosis above the separate responses to each exposure. However, oligodendrocytes in the corpus callosum demonstrated a greater susceptibility to the combined neurotoxic effects of nPM + BCAS exposure.

Hospital Admissions from the Emergency Department and Subsequent Critical Care Interventions for Influenza during Pregnancy.

OBJECTIVE: The objectives of this study were to determine (1) whether obstetrical patients were more likely to be admitted from the emergency department (ED) for influenza compared with nonpregnant women, and (2) require critical care interventions once admitted. STUDY DESIGN: Using data from the 2006 to 2011 Nationwide Emergency Department Sample, ED encounters for influenza for women aged 15 to 54 years without underlying chronic medical conditions were identified. Women were categorized as pregnant or nonpregnant using billing codes. Multivariable log linear models were fit to evaluate the relative risk of admission from the ED and the risk of intensive care unit (ICU)-level interventions including mechanical ventilation and central monitoring with pregnancy status as the exposure of interest. Measures of association were described with adjusted risk ratios (aRRs) with 95% confidence intervals (CIs). RESULTS: We identified 15.9 million ED encounters for influenza of which 4% occurred among pregnant women. Pregnant patients with influenza were nearly three times as likely to be admitted as nonpregnant patients (aRR = 2.99, 95% CI: 2.94, 3.05). Once admitted, obstetric patients were at 72% higher risk of ICU-level interventions (aRR = 1.72, 95% CI: 1.61, 1.84). Of pregnant women admitted from the ED, 9.3% required ICU-level interventions such as mechanical ventilation or central monitoring. Older patients and those with Medicare were also at high risk of admission and ICU-level interventions (p < 0.01). CONCLUSION: Pregnancy confers three times the risk of admission from the ED for influenza and pregnant women are significantly more likely to require ICU-level medical interventions compared with women of similar age. These findings confirm the significant disease burden from influenza in the obstetric population and the public health importance of reducing infection risk. KEY POINTS: · Pregnancy confers three times the risk of admission from the ED for influenza.. · Pregnant women admitted with influenza are significantly more likely to require ICU-level care.. · Influenza represents a significant disease burden in the obstetric population.

Mortality following mechanical thrombectomy for ischemic stroke in patients with COVID-19.

OBJECTIVES: Multiple prior studies have shown a relationship between COVID-19 and strokes; further, COVID-19 has been shown to influence both time-to-thrombectomy and overall thrombectomy rates. Using large-scale, recently released national data, we assessed the association between COVID-19 diagnosis and patient outcomes following mechanical thrombectomy. MATERIALS AND METHODS: Patients in this study were identified from the 2020 National Inpatient Sample. All patients with arterial strokes undergoing mechanical thrombectomy were identified using ICD-10 coding criteria. Patients were further stratified by COVID diagnosis (positive vs. negative). Other covariates, including patient/hospital demographics, disease severity, and comorbidities were collected. Multivariable analysis was used to determine the independent effect of COVID-19 on in-hospital mortality and unfavorable discharge. RESULTS: 5078 patients were identified in this study; 166 (3.3%) were COVID-19 positive. COVID-19 patients had a significantly higher mortality rate (30.1% vs. 12.4%, p < 0.001). When controlling for patient/hospital characteristics, APR-DRG disease severity, and Elixhauser Comorbidity Index, COVID-19 was an independent predictor of increased mortality (OR 1.13, p = 0.002). COVID-19 was not significantly related to discharge disposition (p = 0.480). Older age and increased APR-DRG disease severity were also correlated with increase morality. CONCLUSIONS: Overall, this study indicates that COVID-19 is a predictor of mortality among mechanical thrombectomy. This finding is likely multifactorial but may be related to multisystem inflammation, hypercoagulability, and re-occlusion seen in COVID-19 patients. Further research would be needed to clarify these relationships.

Complications associated with lumbar drain placement for endovascular aortic repair.

OBJECTIVE: We reviewed the complications associated with perioperative lumbar drain (LD) placement for endovascular aortic repair. METHODS: Patients who had undergone perioperative LD placement for endovascular repair of thoracic and thoracoabdominal aortic pathologies from 2010 to 2019 were reviewed. The primary endpoints were major and minor LD-associated complications. Complications that had resulted in neurological sequelae or had required an intervention or a delay in operation were defined as major. These included intracranial hemorrhage, symptomatic spinal hematoma, cerebrospinal fluid (CSF) leak requiring intervention, meningitis, retained catheter tip, arachnoiditis, and traumatic (or bloody) tap resulting in delayed operation. Minor complications were defined as a bloody tap without a delay in surgery, asymptomatic epidural hematoma, and CSF leak with no intervention required. Isolated headaches were recorded separately owing to the minimal clinical impact. RESULTS: A total of 309 LDs had been placed in 268 consecutive patients for 222 thoracic endovascular aortic repairs, 85 complex endovascular aortic repairs (EVARs; fenestrated branched EVAR/parallel grafting), and 2 EVARs (age, 65 ± 13 years; 71% male) for aortic pathology, including aneurysm (47%), dissection (49%), penetrating aortic ulcer (3%), and traumatic injury (0.6%). A dedicated neurosurgical team performed all LD procedures; most were performed by the same individual, with a technical success rate of 98%. Radiologic guidance was required in 3%. The reasons for unsuccessful placement were body habitus (n = 2) and severe spinal disease (n = 3). Most were placed prophylactically (96%). The overall complication rate was 8.1% (4.2% major and 3.9% minor). Major complications included spinal hematoma with paraplegia in 1 patient, intracranial hemorrhage in 2, meningitis in 2, arachnoiditis in 3, CSF leak requiring a blood patch in 3, bloody tap delaying the operation in 1, and a retained catheter tip in 1 patient. Patients who had undergone previous LD placement had experienced significantly more major LD-related complications (12.2% vs 3%; P = .019). The rate of total LD-associated complications did not differ between prophylactic and emergent therapeutic placements (8.1% vs 7.7%; P = 1.00) nor between major or minor complications. On multivariate analysis, previous LD placement and an overweight body mass index were the only independent predictors of major LD-related complications. CONCLUSIONS: The complications associated with LD placement can be severe even when performed by a dedicated team. Previous LD placement and overweight body mass index were associated with a significantly greater risk of complications; however, emergent therapeutic placement was not. Although these risks are justified for therapeutic LD placement, the benefit of prophylactic LD placement to prevent paraplegia should be weighed against these serious complications.

Increasing Prevalence of Frailty and Its Association with Readmission and Mortality Among Hospitalized Patients with IBD.

BACKGROUND: Although age is often used as a clinical risk stratification tool, recent data have suggested that adverse outcomes are driven by frailty rather than chronological age. AIMS: In this nationwide cohort study, we assessed the prevalence of frailty, and factors associated with 30-day readmission and mortality among hospitalized IBD patients. METHODS: Using the Nationwide Readmission Database, we examined all patients with IBD hospitalized from 2010 to 2014. Based on index admission, we defined IBD and frailty using previously validated ICD codes. We used univariable and multivariable regression to assess risk factors associated with all-cause 30-day readmission and 30-day readmission mortality. RESULTS: From 2010 to 2014, 1,405,529 IBD index admissions were identified, with 152,974 (10.9%) categorized as frail. Over this time period, the prevalence of frailty increased each year from 10.20% (27,594) in 2010 to 11.45% (33,507) in 2014. On multivariable analysis, frailty was an independent predictor of readmission (aRR 1.16, 95% CI: 1.14-1.17), as well as readmission mortality (aRR 1.12, 95% CI 1.02-1.23) after adjusting for relevant clinical factors. Frailty also remained associated with readmission after stratification by IBD subtype, admission characteristics (surgical vs. non-surgical), age (patients ≥ 60 years old), and when excluding malnutrition, weight loss, and fecal incontinence as frailty indicators. Conversely, we found older age to be associated with a lower risk of readmission. CONCLUSIONS: Frailty, independent of age, comorbidities, and severity of admission, is associated with a higher risk of readmission and mortality among IBD patients, and is increasing in prevalence. Given frailty is a potentially modifiable risk factor, future studies prospectively assessing frailty within the IBD patient population are needed.

Investigating the blood-spinal cord barrier in preclinical models: a systematic review of in vivo imaging techniques.

STUDY DESIGN: This study is a systematic review. OBJECTIVES: To evaluate current in vivo techniques used in the investigation of the blood-spinal cord barrier (BSCB). METHODS: Search of English language literature for animal studies that investigated the BSCB in vivo. Data extraction included animal model/type, protocol for BSCB evaluation, and study outcomes. Descriptive syntheses are provided. RESULTS: A total of 40 studies were included, which mainly investigated rodent models of experimental autoimmune encephalomyelitis (EAE) or spinal cord injury (SCI). The main techniques used were magnetic resonance imaging (MRI) and intravital microscopy (IVM). MRI served as a reliable tool to longitudinally track BSCB permeability changes with dynamic contrast enhancement (DCE) using gadolinium, or assess inflammatory infiltrations with targeted alternative contrast agents. IVM provided high-resolution visualization of cellular and molecular interactions across the microvasculature, commonly with either epi-fluorescence or two-photon microscopy. MRI and IVM techniques enabled the evaluation of therapeutic interventions and mechanisms that drive spinal cord dysfunction in EAE and SCI. A small number of studies demonstrated the feasibility of DCE-computed tomography, ultrasound, bioluminescent, and fluorescent optical imaging methods to evaluate the BSCB. Technique-specific limitations and multiple protocols for image acquisition and data analyses are described for all techniques. CONCLUSION: There are few in vivo investigations of the BSCB. Additional studies are needed in less commonly studied spinal cord disorders, and to establish standardized protocols for data acquisition and analysis. Further development of techniques and multimodal approaches could overcome current imaging limitations to the spinal cord. These advancements might promote wider adoption of techniques, and can provide greater potential for clinical translation.

Transcranial eddy current damping sensors for detection and imaging of hemorrhagic stroke: feasibility in benchtop experimentation.

OBJECTIVE: Spontaneous intracerebral hemorrhage occurs in an estimated 10% of stroke patients, with high rates of associated mortality. Portable diagnostic technologies that can quickly and noninvasively detect hemorrhagic stroke may prevent unnecessary delay in patient care and help rapidly triage patients with ischemic versus hemorrhagic stroke. As such, the authors aimed to develop a rapid and portable eddy current damping (ECD) hemorrhagic stroke sensor for proposed in-field diagnosis of hemorrhagic stroke. METHODS: A tricoil ECD sensor with microtesla-level magnetic field strengths was constructed. Sixteen gelatin brain models with identical electrical properties to live brain tissue were developed and placed within phantom skull replicas, and saline was diluted to the conductivity of blood and placed within the brain to simulate a hemorrhage. The ECD sensor was used to detect modeled hemorrhages on benchtop models. Data were saved and plotted as a filtered heatmap to represent the lesion location. The individuals performing the scanning were blinded to the bleed location, and sensors were tangentially rotated around the skull models to localize blood. Data were also used to create heatmap images using MATLAB software. RESULTS: The sensor was portable (11.4-cm maximum diameter), compact, and cost roughly $100 to manufacture. Scanning time was 2.43 minutes, and heatmap images of the lesion were produced in near real time. The ECD sensor accurately predicted the location of a modeled hemorrhage in all (n = 16) benchtop experiments with excellent spatial resolution. CONCLUSIONS: Benchtop experiments demonstrated the proof of concept of the ECD sensor for rapid transcranial hemorrhagic stroke diagnosis. Future studies with live human participants are warranted to fully establish the feasibility findings derived from this study.

A systematic review of next-generation point-of-care stroke diagnostic technologies.

OBJECTIVE: Stroke is a leading cause of morbidity and mortality. Current diagnostic modalities include CT and MRI. Over the last decade, novel technologies to facilitate stroke diagnosis, with the hope of shortening time to treatment and reducing rates of morbidity and mortality, have been developed. The authors conducted a systematic review to identify studies reporting on next-generation point-of-care stroke diagnostic technologies described within the last decade. METHODS: A systematic review was performed according to PRISMA guidelines to identify studies reporting noninvasive stroke diagnostics. The QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool was utilized to assess risk of bias. PubMed, Web of Science, and Scopus databases were utilized. Primary outcomes assessed included accuracy and timing compared with standard imaging, potential risks or complications, potential limitations, cost of the technology, size/portability, and range/size of detection. RESULTS: Of the 2646 reviewed articles, 19 studies met the inclusion criteria and included the following modalities of noninvasive stoke detection: microwave technology (6 studies, 31.6%), electroencephalography (EEG; 4 studies, 21.1%), ultrasonography (3 studies, 15.8%), near-infrared spectroscopy (NIRS; 2 studies, 10.5%), portable MRI devices (2 studies, 10.5%), volumetric impedance phase-shift spectroscopy (VIPS; 1 study, 5.3%), and eddy current damping (1 study, 5.3%). Notable medical devices that accurately predicted stroke in this review were EEG-based diagnosis, with a maximum sensitivity of 91.7% for predicting a stroke, microwave-based diagnosis, with an area under the receiver operating characteristic curve (AUC) of 0.88 for differentiating ischemic stroke and intracerebral hemorrhage (ICH), ultrasound with an AUC of 0.92, VIPS with an AUC of 0.93, and portable MRI with a diagnostic accuracy similar to that of traditional MRI. NIRS offers significant potential for more superficially located hemorrhage but is limited in detecting deep-seated ICH (2.5-cm scanning depth). CONCLUSIONS: As technology and computational resources have advanced, several novel point-of-care medical devices show promise in facilitating rapid stroke diagnosis, with the potential for improving time to treatment and informing prehospital stroke triage.

Postpartum Psychiatric Admissions in the United States.

OBJECTIVE: This study aimed to assess risk for postpartum psychiatric admissions in the United States. STUDY DESIGN: This study used the 2010 to 2014 Nationwide Readmissions Database to identify psychiatric admissions during the first 60 days after delivery hospitalization. Timing of admission after delivery discharge was determined. We fit multivariable log-linear regression models to assess the impact of psychiatric comorbidity on admission risk, adjusting for patient, obstetrical, and hospital factors. RESULTS: Of 15.7 million deliveries from 2010 to 2014, 11,497 women (0.07%) were readmitted for a primary psychiatric diagnosis within 60 days postpartum. Psychiatric admissions occurred relatively consistently across 10-day periods after delivery hospitalization discharge. Psychiatric diagnoses were present among 5% of women at delivery but 40% of women who were readmitted postpartum for a psychiatric indication. In the adjusted model, women with psychiatric diagnoses at delivery hospitalization were 9.7 times more likely to be readmitted compared with those without psychiatric comorbidity. Women at highest risk for psychiatric admission were those with Medicare and Medicaid, in lower income quartiles, and of younger age. CONCLUSION: While a large proportion of psychiatric admissions occurred among a relatively small proportion of at-risk women, admissions occurred over a broad temporal period relative to other indications for postpartum admission.

Acute Venous Thromboembolism Risk Highest Within 60 Days After Discharge From the Hospital in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) have a high risk of venous thromboembolism (VTE). We assessed the timing and risk factors associated with readmission to the hospital for VTE among patients with IBD. METHODS: We collected data from the Nationwide Readmissions Database on IBD index admissions resulting in readmission to the hospital for VTE within 60 days, from 2010 through 2014. We used univariable and multivariable regression to assess risk factors associated with VTE readmission with unadjusted risk ratio (RR) and adjusted RR (aRR) as measures of effect. Time to VTE readmission was assessed in 10-day intervals, for up to 90 days. RESULTS: We identified 872,122 index admissions of patients with IBD; 1160 resulted in readmission with VTE. More than 90% of readmissions occurred within 60 days of discharge from the index admission. Factors associated with hospital readmission with VTE included prior VTE, longer length of hospital stay, comorbidities, having a flexible sigmoidoscopy or colonoscopy at index admission, and age older than 18 years. Additional risk factors included Clostridium difficile infection at index admission (aRR, 1.47; 95% CI, 1.17-1.85) and discharge to a skilled nursing facility or intermediate care facility (aRR, 1.39; 95% CI, 1.14-1.70) or discharge with home health services (aRR, 1.65; 95% CI, 1.41-1.94). CONCLUSIONS: Among patients admitted to the hospital with IBD, most readmissions with VTE occur within 60 days of discharge. Readmission with VTE is associated with C difficile infection and discharge to a skilled nursing facility, intermediate care facility, or with home health services. Studies are needed to evaluate the potential benefit of extending VTE prophylaxis for patients admitted to the hospital with IBD for up to 2 months after discharge, to minimize risk.

Cyclic-AMP induces Nogo-A receptor NgR1 internalization and inhibits Nogo-A-mediated collapse of growth cone.

The promotion of axonal regeneration is required for functional recovery from stroke and various neuronal injuries. However, axonal regeneration is inhibited by diverse axonal growth inhibitors, such as Nogo-A. Nogo-66, a C-terminal domain of Nogo-A, binds to the Nogo-A receptor 1 (NgR1) and induces the collapse of growth cones and inhibits neurite outgrowth. NgR1 is also a receptor for additional axonal growth inhibitors, suggesting it is an important target for the prevention of axonal growth inhibition. By using the indirect immunofluorescence method, we show for the first time that a cell-permeable cAMP analog (dibutyryl-cAMP) induced a rapid decrease in the cell surface expression of NgR1 in Neuroscreen-1 (NS-1) cells. The biotinylation method revealed that cAMP indeed induced internalization of NgR1 within minutes. Other intracellular cAMP-elevating agents, such as forskolin, which directly activates adenylyl cyclase, and rolipram, which inhibits cyclic nucleotide phosphodiesterase, also induced this process. This internalization was found to be reversible and influenced by intracellular levels of cAMP. Using selective activators and inhibitors of protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac), we found that NgR1 internalization is independent of PKA, but dependent on Epac. The decrease in cell surface expression of NgR1 desensitized NS-1 cells to Nogo-66-induced growth cone collapse. Therefore, it is likely that besides axonal growth inhibitors affecting neurons, neurons themselves also self-regulate their sensitivity to axonal growth inhibitors, as influenced by intracellular cAMP/Epac. This normal cellular regulatory mechanism may be pharmacologically exploited to overcome axonal growth inhibitors, and enhance functional recovery after stroke and neuronal injuries.

Fragmentation of postpartum readmissions in the United States.

BACKGROUND: Fragmentation of care, wherein a patient is readmitted to a hospital different from the initial point of care, has been shown to be associated with worse patient outcomes in other medical specialties. However, postpartum fragmentation of care has not been well characterized in obstetrics. OBJECTIVE: To characterize risk for and outcomes associated with fragmentation of postpartum readmissions wherein the readmitting hospital is different than the delivery hospital. METHODS: The 2010 to 2014 Nationwide Readmissions Database was used for this retrospective cohort study. Postpartum readmissions within 60 days of delivery hospitalization discharge for women aged 15-54 years were identified. The primary outcome, fragmentation, was defined as readmission to a different hospital than the delivery hospital. Hospital, demographic, medical, and obstetric factors associated with fragmented readmission were analyzed. Adjusted log-linear models were performed to analyze risk for readmission with adjusted risk ratios and 95% confidence intervals as the measures of effect. The associations between fragmentation and secondary outcomes including (1) length of stay >90th percentile, (2) hospitalization costs >90th percentile, and (3) severe maternal morbidity were determined. Whether specific indications for readmission such as hypertensive diseases of pregnancy, wound complications, and other conditions were associated with higher or lower risk for fragmentation was analyzed. RESULTS: From 2010 to 2014, 141,276 60-day postpartum readmissions were identified, of which 15% of readmissions (n = 21,789) occurred at a hospital different from where the delivery occurred. Evaluating individual readmission indications, fragmentation was less likely for hypertension (11.1%), wound complications (10.7%), and uterine infections (11.0%), and more likely for heart failure (28.6%), thromboembolism (28.4%), and upper respiratory infections (33.9%) (P < .01 for all). In the adjusted analysis, factors associated with fragmentation included public insurance compared to private insurance (Medicare: adjusted risk ratio, 1.68; 95% confidence interval, 1.52, 1.86; Medicaid: adjusted risk ratio, 1.28; 95% confidence interval, 1.24, 1.32). Fragmentation was associated with increased risk for severe maternal morbidity during readmissions in both unadjusted (relative risk, 1.84; 95% confidence interval, 1.79, 1.89) and adjusted (adjusted risk ratio, 1.81; 95% confidence interval, 1.76, 1.86) analyses. In adjusted analyses, fragmentation was also associated with increased risk for length of stay >90th percentile (relative risk, 1.48; 95% confidence interval, 1.42-1.54) and hospitalization costs >90th percentile (adjusted risk ratio, 1.74; 95% confidence interval, 1.67, 1.81). CONCLUSION: This study of nationwide estimates of postpartum fragmentation found discontinuity of postpartum care was associated with increased risk for severe morbidity, high costs, and long length of stay. Reduction of fragmentation may represent an important goal in overall efforts to improve postpartum care.

Increased 30-day readmission rate after craniotomy for tumor resection at safety net hospitals in small metropolitan areas.

PURPOSE: Unplanned readmission of post-operative brain tumor patients is often attributed to hospital and patient characteristics and is associated with higher mortality and cost. Previous studies demonstrate multiple patient outcome disparities in safety net hospitals (SNHs) when compared to non-SNHs. This study uses the Nationwide Readmissions Database (NRD) to determine if initial brain tumor resection at SNHs is associated with increased 30-day non-elective readmission rates. METHODS: Patients with benign or malignant primary or metastatic brain tumor undergoing craniotomy for surgical resection were retrospectively identified in the NRD from 2010 to 2014. SNHs were defined as hospitals with Medicaid and uninsured patient burden in the top quartile. Descriptive and multivariate analyses employing survey-adjusted logistic regression evaluated patient and hospital level factors influencing 30-day readmissions. RESULTS: During the study period, 83,367 patients met inclusion criteria. 44.7% of patients had a benign tumor, and 55.3% had a malignant tumor. Secondary CNS neoplasm (5.99%), post-operative infection (5.96%), and septicemia (4.26%) caused most readmissions within 30 days. Patients had increased unplanned readmission rates if they underwent craniotomy for tumor resection at a SNH in a small metropolitan area (OR 1.11, 95% CI 1.02-1.21, p = 0.01), but not at a SNH in a large metropolitan area (OR 0.99, 95% CI 0.93-1.05, p = 0.73). CONCLUSION: This finding may reflect differences in access to care and disparities in neurosurgical resources between small and large metropolitan areas. Inequities in expertise and capacity are relevant as surgical volume was also related to readmission rates. Further studies may be warranted to address such disparities.

Effects of ambient particulate matter on vascular tissue: a review.

Fine and ultra-fine particulate matter (PM) are major constituents of urban air pollution and recognized risk factors for cardiovascular diseases. This review examined the effects of PM exposure on vascular tissue. Specific mechanisms by which PM affects the vasculature include inflammation, oxidative stress, actions on vascular tone and vasomotor responses, as well as atherosclerotic plaque formation. Further, there appears to be a greater PM exposure effect on susceptible individuals with pre-existing cardiovascular conditions.

Comorbid depression associated with non-routine discharge following craniotomy for low-grade gliomas and benign tumors - a nationwide readmission database analysis.

PURPOSE: Prior studies have demonstrated elevated rates of depression in patients with malignant brain tumor; however, the prevalence and effect on surgical outcomes in patients with low-grade gliomas (LGG) and benign brain tumors (BBT) remain unknown. Readmission and non-routine discharge, which includes discharge to skilled nursing, rehabilitative, and other inpatient facilities, are well-established quality of care indicators. We sought to analyze the association between comorbid depression and non-routine discharge, readmission, and other post-operative inpatient outcomes in patients with LGG and BBT. METHODS: The Nationwide Readmissions Database from 2010 to 2014 was retrospectively queried to select for surgically treated patients with LGG and BBT. Multivariable logistic regression models adjusting for patient and hospital characteristics were used to determine the effects of comorbid depression on post-operative outcomes. Interaction of gender and depression on non-routine disposition was analyzed. RESULTS: We identified 31,654 craniotomies for resection of BBT and LGG (2010-2014). The majority of patients (64.1%) were female. The rate of depression comorbid with BBT and LGG was 11.9%. Depression was associated with non-routine discharge after surgery (OR 1.19, p 0.0002*), but was not associated with increased morbidity, mortality, or readmission at 30 or 90 days. The rate of comorbid depression was higher among female than male patients (14.0 vs. 8.0%). Depression in males was associated with a 38% increased likelihood of non-routine disposition (p = 0.0002*), while depression in females was associated with a 13% increased likelihood of non-routine disposition (p = 0.03*). CONCLUSION: Depression is prevalent in patients with LGG and BBT and is associated with increased risk of non-routine discharge following surgical intervention. The increased likelihood of non-routine disposition is greater for males than that for females. Awareness of the risk factors for depression may aid in early screening and intervention and improve overall patient outcomes.

Predictors of readmission after craniotomy for meningioma resection: a nationwide readmission database analysis.

BACKGROUND: Meningiomas are the most common benign primary brain tumors. The mainstay of treatment, surgical resection, is often curative. Given the excellent prognosis of these lesions, minimizing perioperative complications is of the utmost importance. With the establishment of the National Readmissions Database (NRD), researchers are now able to identify variables associated with postoperative complications beyond the index admission. OBJECTIVE: In this study, we sought to identify the leading causes for non-elective readmission and variables associated with increased likelihood of readmission at 30 and 90 days after discharge following a craniotomy for meningioma resection. METHODS: Adult inpatients who underwent craniotomy for meningioma resection between 2010 and 2014 were queried from the NRD. All-cause readmissions following craniotomy at 30 and 90 days were identified, and a multivariable logistic regression model was used to characterize independent risk factors. RESULTS: Among 26,034 patients who received craniotomy for meningioma resection, 2825 (10.9%) were readmitted at 30 days and 3436 (16.1%) were readmitted at 90 days. Postoperative wound infection was the most common readmission diagnosis, occurring in 9.32% and 10.2% of 30- and 90-day readmissions respectively. Patient factors associated with increased likelihood of readmission included male gender, greater illness severity, non-routine discharge, index length of hospitalization, and having Medicare or Medicaid insurance. CONCLUSIONS: Readmission following craniotomy for meningioma resection occurs at a clinically significant rate. Several patient factors were identified in association with all-cause 30- and 90-day readmissions. Further studies are required to identify means for preventing complications following discharge in these vulnerable patient populations.

Risk of Stillbirth after Antepartum Hospitalization for Hypertensive Diseases of Pregnancy.

OBJECTIVE: To determine if women with an antepartum admission for hypertensive diseases of pregnancy (HDP) were at increased risk for stillbirth. STUDY DESIGN: This study utilized the 2010 to 2014 Nationwide Readmissions Database. Antepartum admissions with HDP were identified and linked to subsequent delivery hospitalizations. Delivery hospitalizations with HDP without a preceding antepartum HDP admission were also identified. Risk for stillbirth, abruption, or both was compared between these two groups. RESULTS: An estimated 382,621 deliveries with an HDP diagnosis were identified of which 14,857 (3.9%) had a preceding antepartum admission for HDP. Stillbirth occurred in 7.8 per 1,000 delivery hospitalizations complicated by HDP with risk higher with a preceding HDP antepartum admission in both unadjusted (1.1 vs. 0.8%, risk ratios [RR] 1.46, 95% confidence interval [CI] 1.24-1.70) and adjusted (adjusted risk ratios [aRR] 1.24, 95% CI 1.06, 1.46) analyses. Abruption occurred in 19.6 per 1,000 delivery hospitalizations complicated by HDP with risk higher with a preceding HDP antepartum admission in both unadjusted (2.5 vs. 1.9%, RR 1.30, 95% CI 1.17-1.44) and adjusted (aRR 1.24, 95% CI 1.11, 1.37) analyses. Risk for combined abruption and stillbirth did not differ significantly. CONCLUSION: In this analysis, prior antenatal hospitalization was associated with increased risk for stillbirth among women with HDP.