Implementation of Gate-All-Around Gate-Engineered Charge Plasma Nanowire FET-Based Common Source Amplifier.

This paper examines the performance of a Gate-Engineered Gate-All-Around Charge Plasma Nanowire Field Effect Transistor (GAA-DMG-GS-CP NW-FET) and the implementation of a common source (CS) amplifier circuit. The proposed GAA-DMG-GS-CP NW-FET incorporates dual-material gate (DMG) and gate stack (GS) as gate engineering techniques and its analog/RF performance parameters are compared to those of the Gate-All-Around Single-Material Gate Charge Plasma Nanowire Field Effect Transistor (GAA-SMG-CP NW-FET) device. Both Gate-All-Around (GAA) devices are designed using the Silvaco TCAD tool. GAA structures have demonstrated good gate control because the gate holds the channel, which is an inherent advantage for both devices discussed herein. The charge plasma dopingless technique is used, in which the source and drain regions are formed using metal contacts and necessary work functions rather than doping. This dopingless technique eliminates the need for doping, reducing fluctuations caused by random dopants and lowering the device's thermal budget. Gate engineering techniques such as DMG and GS significantly improved the current characteristics which played a crucial role in obtaining maximum gain for circuit designs. The lookup table (LUT) approach is used in the implementation of the CS amplifier circuit with the proposed device. The transient response of the circuit is analyzed with both the device structures where the gain achieved for the CS amplifier circuit using the proposed GAA-DMG-GS-CP NW-FET is 15.06 dB. The superior performance showcased by the proposed GAA-DMG-GS-CP NW-FET device with analog, RF and circuit analysis proves its strong candidature for future nanoscale and low-power applications.

Dendrimer-enabled targeted delivery attenuates glutamate excitotoxicity and improves motor function in a rabbit model of cerebral palsy.

Glutamate carboxypeptidase II (GCPII), localized on the surface of astrocytes and activated microglia, regulates extracellular glutamate concentration in the central nervous system (CNS). We have previously shown that GCPII is upregulated in activated microglia in the presence of inflammation. Inhibition of GCPII activity could reduce glutamate excitotoxicity, which may decrease inflammation and promote a 'normal' microglial phenotype. 2-(3-Mercaptopropyl) pentanedioic acid (2-MPPA) is the first GCPII inhibitor that underwent clinical trials. Unfortunately, immunological toxicities have hindered 2-MPPA clinical translation. Targeted delivery of 2-MPPA specifically to activated microglia and astrocytes that over-express GCPII has the potential to mitigate glutamate excitotoxicity and attenuate neuroinflammation. In this study, we demonstrate that 2-MPPA when conjugated to generation-4, hydroxyl-terminated polyamidoamine (PAMAM) dendrimers (D-2MPPA) localize specifically in activated microglia and astrocytes only in newborn rabbits with cerebral palsy (CP), not in controls. D-2MPPA treatment led to higher 2-MPPA levels in the injured brain regions compared to 2-MPPA treatment, and the extent of D-2MPPA uptake correlated with the injury severity. D-2MPPA was more efficacious than 2-MPPA in decreasing extracellular glutamate level in ex vivo brain slices of CP kits, and in increasing transforming growth factor beta 1 (TGF-ß1) level in primary mixed glial cell cultures. A single systemic intravenous dose of D-2MPPA on postnatal day 1 (PND1) decreased microglial activation and resulted in a change in microglial morphology to a more ramified form along with amelioration of motor deficits by PND5. These results indicate that targeted dendrimer-based delivery specifically to activated microglia and astrocytes can improve the efficacy of 2-MPPA by attenuating glutamate excitotoxicity and microglial activation.

Selected Transesophageal Echocardiographic Parameters of Left Ventricular Diastolic Function Predict Length of Stay Following Coronary Artery Bypass Graft-A Prospective Observational Study.

(1) Importance: Abnormal left ventricular (LV) diastolic function, with or without a diagnosis of heart failure, is a common finding that can be easily diagnosed by intra-operative transesophageal echocardiography (TEE). The association of diastolic function with duration of hospital stay after coronary artery bypass (CAB) is unknown. (2) Objective: To determine if selected TEE parameters of diastolic dysfunction are associated with length of hospital stay after coronary artery bypass surgery (CAB). (3) Design: Prospective observational study. (4) Setting: A single tertiary academic medical center. (5) Participants: Patients with normal systolic function undergoing isolated CAB from September 2017 through June 2018. (6) Exposures: LV function during diastole, as assessed by intra-operative TEE prior to coronary revascularization. (7) Main Outcomes and Measures: The primary outcome was duration of postoperative hospital stay. Secondary intermediate outcomes included common postoperative cardiac, respiratory, and renal complications. (8) Results: The study included 176 participants (mean age 65.2 ± 9.2 years, 73% male); 105 (60.2%) had LV diastolic dysfunction based on selected TEE parameters. Median time to hospital discharge was significantly longer for subjects with selected parameters of diastolic dysfunction (9.1/IQR 6.6−13.5 days) than those with normal LV diastolic function (6.5/IAR 5.3−9.7 days) (p < 0.001). The probability of hospital discharge was 34% lower (HR 0.66/95% CI 0.47−0.93) for subjects with diastolic dysfunction based on selected TEE parameters, independent of potential confounders, including a baseline diagnosis of heart failure. There was a dose−response relation between severity of diastolic dysfunction and probability of discharge. LV diastolic dysfunction based on those selected TEE parameters was also associated with postoperative cardio-respiratory complications; however, these complications did not fully account for the relation between LV diastolic dysfunction and prolonged length of hospital stay. (9) Conclusions and Relevance: In patients with normal systolic function undergoing CAB, diastolic dysfunction based on selected TEE parameters is associated with prolonged duration of postoperative hospital stay. This association cannot be explained by baseline comorbidities or common post-operative complications. The diagnosis of diastolic dysfunction can be made by TEE.

Nasal Microbiota and Infectious Complications After Elective Surgical Procedures.

Importance: The association of the nasal microbiome with outcomes in surgical patients is poorly understood. Objective: To characterize the composition of nasal microbiota in patients undergoing clean elective surgical procedures and to examine the association between characteristics of preoperative nasal microbiota and occurrence of postoperative infection. Design, Setting, and Participants: Using a nested matched case-control design, 53 individuals who developed postoperative infection were matched (approximately 3:1 by age, sex, and surgical procedure) with 144 individuals who were not infected (ie, the control group). The 2 groups were selected from a prospective cohort of patients undergoing surgical procedures at 2 tertiary care university hospitals in Baltimore, Maryland, who were at high risk for postoperative infectious complications. Included individuals were aged 40 years or older; had no history of autoimmune disease, immunocompromised state, immune-modulating medication, or active infection; and were scheduled to undergo elective cardiac, vascular, spinal, or intracranial surgical procedure. Data were analyzed from October 2015 through September 2020. Exposures: Nasal microbiome cluster class served as the main exposure. An unsupervised clustering method (ie, grades of membership modeling) was used to classify nasal microbial samples into 2 groups based on features derived from 16S ribosomal RNA gene sequencing. The microbiome cluster groups were derived independently and agnostic of baseline clinical characteristics and infection status. Main Outcomes and Measures: Composite of surgical site infection, bacteremia, and pneumonia occurring within 6 months after surgical procedure. Results: Among 197 participants (mean [SD] age, 64.1 [10.6] years; 63 [37.7%] women), 553 bacterial taxa were identified from preoperative nasal swab samples. A 2-cluster model (with 167 patients in cluster 1 and 30 patients in cluster 2) accounted for the largest proportion of variance in microbial profiles using grades of membership modeling and was most parsimonious. After adjusting for potential confounders, the probability of assignment to cluster 2 was associated with 6-fold higher odds of infection after surgical procedure (odds ratio [OR], 6.18; 95% CI, 3.33-11.7; P < .001) independent of baseline clinical characteristics, including nasal carriage of Staphylococcus aureus. Intrasample (ie, α) diversity was inversely associated with infectious outcome in both clusters (OR, 0.57; 95% CI, 0.42-0.75; P < .001); however, probability of assignment to cluster 2 was associated with higher odds of infection independent of α diversity (OR, 4.61; 95% CI, 2.78-7.86; P < .001). Conclusions and Relevance: These findings suggest that the nasal microbiome was an independent risk factor associated with infectious outcomes among individuals who underwent elective surgical procedures and may serve as a biomarker associated with infection susceptibility in this population.

Diagnostic Discordance in Pediatric Critical Care Transport: A Single-Center Experience.

OBJECTIVES: The aims of the study were to describe diagnostic discordance rates at our pediatric tertiary care center between the reason for transfer of critically ill/injured children (determined by the referring institution) and the inpatient admission diagnosis (determined by our accepting institution), to identify potential factors associated with discordance, and to determine its impact on patient outcomes. METHODS: We conducted a retrospective chart review of all critically ill/injured children transferred to the Johns Hopkins Children's Center between July 1, 2017, and June 30, 2018. All patients whose initial inpatient disposition was the pediatric intensive care unit were included. RESULTS: Six hundred forty-three children (median age, 51 months) from 57 institutions (median pediatric capability level: 3) met inclusion criteria: 46.8% were transported during nighttime, 86.5% by ground, and 21.2% accompanied by a physician. Nearly half (43.4%) had respiratory admission diagnoses. The rest included surgical/neurosurgical (14.2%), neurologic (11.2%), cardiovascular/shock (8.7%), endocrine (8.2%), infectious disease (6.8%), poisoning (3.1%), hematology-oncology (2.2%), gastrointestinal/metabolic (1.9%), and renal (0.3%). Forty-six (7.2%) had referral-to-admission diagnostic discordance: 25 of 46 had discordance across different diagnostic groups and 21 of 46 had clinically significant discordance within the same diagnostic group. The discordant group had higher need for respiratory support titration in transport (43.9% vs 27.9%, p = 0.02); more invasive procedures and vasopressor needs during the day of admission (26.1% vs 11.6%, P = 0.008; 19.6% vs 7%, P = 0.006); and longer intensive care unit (ICU) and hospital stays (5 vs 2 days; 11 vs 3 days, P < 0.001). When compared with respiratory admission diagnoses, patients with cardiovascular/shock and neurologic diagnoses were more likely to have discordant diagnoses (odds ratio [95% confidence interval], 13.24 [5.41-35.05]; 6.47 [2.48-17.75], P < 0.001). CONCLUSIONS: Seven percent of our critically ill/injured pediatric cohort had clinically significant referral-to-admission diagnostic discordance. Patients with cardiovascular/shock and neurologic diagnoses were particularly at risk. Those with discordant diagnoses had more in-transit events; a higher need for ICU interventions postadmission; and significantly longer ICU stays and hospitalizations, deserving further investigation.

Continuous Electroencephalographic Monitoring in the Intensive Care Unit: A Cross-Sectional Study.

OBJECTIVE: Research on continuous electro-encephalographic monitoring (cEEG) in the intensive care unit (ICU) has previously focused on neuroscience ICUs. This study determines cEEG utilization within a sample of specialty ICUs world-wide. METHODS: A cross-sectional electronic survey of attending level physicians across various intensive care settings. Twenty-five questions developed from consensus statements on the use of cEEG in the critically ill sent as an electronic survey. RESULTS: Of all, 9344 were queried and 417 (4.5%) responses were analyzed with 309 (74%) from the United States and 74 (18%) internationally. Intensive care units were: medical (10%), surgical (6%), neurologic/neurosurgical (12%), cardiac (4%), trauma (3%), pediatrics (29%), burn (<1%), multidisciplinary (30%), and other (5%). Intensive care units were: academic (65%), community (18%), public (3%), military (1%), and other (13%). Specialized cEEG teams were available in 71% of ICUs. Rapid 24/7 access and cEEG interpretation was available in 32% of ICUs. Interpretation changed clinical management frequently (28%) and sometimes (45%). CONCLUSIONS: Despite guideline recommendations for cEEG use, there is a discordance between availability, night coverage, and immediate interpretation. Only 27% have institutional protocols for indications and duration of cEEG monitoring. Furthermore, cEEG may be underutilized in nonneurologic ICUs as well as ICUs in smaller nonacademic affiliated hospitals and those outside of the United States.

Addressing the Opioid Crisis One Surgical Patient at a Time: Outcomes of a Novel Perioperative Pain Program.

Opioid prescriptions in the surgical setting have been implicated as contributors to the opioid epidemic. The authors hypothesized that a multidisciplinary approach to perioperative pain management for patients on chronic opioid therapy could decrease postoperative opioid requirements while reducing postoperative pain scores and improving functional outcomes. Therefore, a Perioperative Pain Program (PPP) for chronic opioid users was implemented. This study presents outcomes from the first 9 months of the PPP. Sixty-one patients met the inclusion criteria. Opioid consumption in morphine milligram equivalent (MME) was calculated and physical and health status of patients was assessed with the Brief Pain Inventory, Short-Form McGill Pain Questionnaire, and Short Form-12. Preliminary results showed significant reduction in MME, improved pain scores, and improved function for surgical patients on chronic opioids. PPP effectively reduced opioid usage without negatively influencing patient-reported outcomes, such as physical pain score assessment and health-related quality of life.

Integrating Advance Care Planning Videos into Surgical Oncologic Care: A Randomized Clinical Trial.

Background: Preoperative advance care planning (ACP) may benefit patients undergoing major surgery. Objective: To evaluate feasibility, safety, and early effectiveness of video-based ACP in a surgical population. Design: Randomized controlled trial with two study arms. Setting: Single, academic, inner-city tertiary care hospital. Subjects: Patients undergoing major cancer surgery were recruited from nine surgical clinics. Of 106 consecutive potential participants, 103 were eligible and 92 enrolled. Interventions: In the intervention arm, patients viewed an ACP video developed by patients, surgeons, palliative care clinicians, and other stakeholders. In the control arm, patients viewed an informational video about the hospital's surgical program. Measurements: Primary Outcomes-ACP content and patient-centeredness in patient-surgeon preoperative conversation. Secondary outcomes-patient Hospital Anxiety and Depression Scale (HADS) score; patient goals of care; patient and surgeon satisfaction; video helpfulness; and medical decision maker designation. Results: Ninety-two patients (target enrollment: 90) were enrolled. The ACP video was successfully integrated with no harm noted. Patient-centeredness was unchanged (incidence rate ratio [IRR] = 1.06, confidence interval [0.87-1.3], p = 0.545), although there were more ACP discussions in the intervention arm (23% intervention vs. 10% control, p = 0.18). While slightly underpowered, study results did not signal that further enrollment would have yielded statistical significance. There were no differences in secondary outcomes other than the intervention video was more helpful (p = 0.007). Conclusions: The ACP video was successfully integrated into surgical care without harm and was thought to be helpful, although video content did not significantly change the ACP content or patient-surgeon communication. Future studies could increase the ACP dose through modifying video content and/or who presents ACP. Trial Registration: clinicaltrials.gov Identifier NCT02489799.

Efficacy and Cost Comparison of Case-based Learning to Simulation-based Learning for Teaching Malignant Hyperthermia Concepts to Anesthesiology Residents.

BACKGROUND: Case-based learning (CBL) is a distinct classroom-based teaching format. We compare learning and retention using a CBL teaching strategy vs simulation-based learning (SBL) on the topic of malignant hyperthermia. METHODS: In this study, 54 anesthesia residents were assigned to either a CBL or SBL experience. All residents had prior simulation experience, and both groups received a pretest and a lecture on rare diseases with emphasis on malignant hyperthermia followed by a CBL or SBL session. Test questions were validated for face and construct validity. Postsession testing occurred on the same day and at 4 months. RESULTS: Twenty-seven residents completed all components of the study. The CBL group had 10 residents, and the SBL group had 17 residents. Most residents (80%) had previous exposure to malignant hyperthermia education. ANOVA for repeated measures demonstrated superior learning and long-term retention in the CBL group. In addition, our cost analysis reveals the cost of SBL to be approximately 17 times more expensive per learner than CBL. CONCLUSIONS: We found that CBL promoted learning and long-term retention for the topic of malignant hyperthermia and it is a more affordable teaching method. Affordability and effectiveness evidence may guide some programs toward CBL, particularly if access to simulation is limited. The number of participants and full validation of the examination questions are limitations of the study. Further studies are required to validate the findings of this study.

Dendrimer-N-acetyl-L-cysteine modulates monophagocytic response in adrenoleukodystrophy.

OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder due to mutations in the peroxisomal very long-chain fatty acyl-CoA transporter, ABCD1, with limited therapeutic options. ALD may manifest in a slowly progressive adrenomyeloneuropathy (AMN) phenotype, or switch to rapid inflammatory demyelinating cerebral disease (cALD), in which microglia have been shown to play a pathophysiological role. The aim of this study was to determine the role of patient phenotype in the immune response of ex vivo monophagocytic cells to stimulation, and to evaluate the efficacy of polyamidoamine dendrimer conjugated to the antioxidant precursor N-acetyl-cysteine (NAC) in modulating this immune response. METHODS: Human monophagocytic cells were derived from fresh whole blood, from healthy (n = 4), heterozygote carrier (n = 4), AMN (n = 7), and cALD (n = 4) patients. Cells were exposed to very long-chain fatty acids (VLCFAs; C24:0 and C26:0) and treated with dendrimer-NAC (D-NAC). RESULTS: Ex vivo exposure to VLCFAs significantly increased tumor necrosis factor α (TNFα) and glutamate secretion from cALD patient macrophages. Additionally, a significant reduction in total intracellular glutathione was observed in cALD patient cells. D-NAC treatment dose-dependently reduced TNFα and glutamate secretion and replenished total intracellular glutathione levels in cALD patient macrophages, more efficiently than NAC. Similarly, D-NAC treatment decreased glutamate secretion in AMN patient cells. INTERPRETATION: ALD phenotypes display unique inflammatory profiles in response to VLCFA stimulation, and therefore ex vivo monophagocytic cells may provide a novel test bed for therapeutic agents. Based on our findings, D-NAC may be a viable therapeutic strategy for the treatment of cALD. Ann Neurol 2018;84:452-462.

Family companions' involvement during pre-surgical consent visits for major cancer surgery and its relationship to visit communication and satisfaction.

OBJECTIVE: To examine the association between family companion presence during pre-surgical visits to discuss major cancer surgery and patient-provider communication and satisfaction. METHODS: Secondary analysis of 61 pre-surgical visit recordings with eight surgical oncologists at an academic tertiary care hospital using the Roter Interaction Analysis System (RIAS). Surgeons, patients, and companions completed post-visit satisfaction questionnaires. Poisson and logistic regression models assessed differences in communication and satisfaction when companions were present vs. absent. RESULTS: There were 46 visits (75%) in which companions were present, and 15 (25%) in which companions were absent. Companion communication was largely emotional and facilitative, as measured by RIAS. Companion presence was associated with more surgeon talk (IRR 1.29, p = 0.006), and medical information-giving (IRR 1.41, p = 0.001). Companion presence was associated with less disclosure of lifestyle/psychosocial topics by patients (IRR 0.55, p = 0.037). In adjusted analyses, companions' presence was associated with lower levels of patient-centeredness (IRR 0.77, p 0.004). There were no differences in patient or surgeon satisfaction based on companion presence. CONCLUSION: Companions' presence during pre-surgical visits was associated with patient-surgeon communication but was not associated with patient or surgeon satisfaction. PRACTICE IMPLICATIONS: Future work is needed to develop interventions to enhance patient-companion-provider interactions in this setting.

Correction to: Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.

After publication of the article [1], it has been brought to our attention that an author's name has been formatted incorrectly.

Cervical Epidural Depth: Correlation Between Cervical MRI Measurements of the Skin-to-Cervical Epidural Space and the Actual Needle Depth During Interlaminar Cervical Epidural Injections.

Objective: The purpose of this study was to assess the correlation between skin-to-epidural space depth, as measured on cervical magnetic resonance imaging (MRI), and actual needle depth, as measured by Tuohy needle markings during cervical epidural steroid injections. Methods: We conducted a retrospective review of cervical MRI images to determine estimated depth from skin to epidural space. Of the 121 reviewed patients who underwent cervical epidural steroid injections, 81 met inclusion criteria and were retained for data analysis. Results: At the C6-C7 level, the estimated needle depth according to MRI images was 6.03 ± 1.15 cm (mean ± SD) and the actual needle depth was 5.62 ± 0.77 cm. At the C7-T1 level, the estimated needle depth based on MRI images was 5.90 ± 1.05 cm and the actual needle depth was 5.73 ± 0.98 cm. At both C6-C7 and C7-T1, MRI depth (P < 0.009, P < 0.001) and body mass index (P < 0.001, P < 0.002) were significantly associated with actual depth. Conclusions: Estimates of needle depth made with MRI were consistently slightly deeper than the actual loss-of-resistance needle depth, indicating that the provider should employ caution when using MRI predictive depths. Information garnered from preprocedure MRIs can be used to improve the safety of cervical epidural steroid injection procedures.

Trajectory of inflammatory and microglial activation markers in the postnatal rabbit brain following intrauterine endotoxin exposure.

BACKGROUND: Maternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks. METHODS: Timed pregnant New Zealand white rabbits underwent laparotomy on gestational day 28 (G28). They were randomly divided to receive lipopolysaccharide (LPS; 20µg/kg in 1mL saline) (Endotoxin group) or saline (1mL) (control saline, CS group), administrated along the wall of the uterus. The PVR from the CS and Endotoxin kits were harvested at G29 (1day post-injury), postnatal day1 (PND1, 3day post-injury) and PND5 (7days post-injury) for real-time PCR, ELISA and immunohistochemistry. Kits from CS and Endotoxin groups underwent longitudinal MicroPET imaging, with [11C]PK11195, a tracer for microglial activation. RESULTS: We found that intrauterine endotoxin exposure resulted in pro-inflammatory microglial activation in the PVR of rabbits in the first postnatal week. This was evidenced by increased TSPO (translocator protein) expression co-localized with microglia/macrophages in the PVR, and changes in the microglial morphology (ameboid soma and retracted processes). In addition, CD11b level significantly increased with a concomitant decline in the CD45 level in the PVR at G29 and PND1. There was a significant elevation of pro-inflammatory cytokines and iNOS, and decreased anti-inflammatory markers in the Endotoxin kits at G29, PND1 and PND5. Increased [11C]PK11195 binding to the TSPO measured in vivo by PET imaging in the brain of Endotoxin kits was present up to PND14-17. CONCLUSIONS: Our results indicate that a robust pro-inflammatory microglial phenotype/brain milieu commenced within 24h after LPS exposure and persisted through PND5 and in vivo TSPO binding was found at PND14-17. This suggests that there may be a window of opportunity to treat after birth. Therapies aimed at inducing an anti-inflammatory phenotype in microglia might promote recovery in maternal inflammation induced neonatal brain injury.

Anti-aging factor, serum alpha-Klotho, as a marker of acute physiological stress, and a predictor of ICU mortality, in patients with septic shock.

PURPOSE: Genetic deletions decreasing serum alpha-Klotho (alpha-KL) have been associated with rapid aging, multi-organ failure and increased mortality in experimental sepsis. We hypothesized that lower alpha-KL obtained at the onset of septic shock correlates with higher mortality. MATERIALS AND METHODS: Prospective cohort of 104 adult patients with septic shock. Alpha-KL was measured via ELISA on serum collected on the day of enrollment (within 72h from the onset of shock). Relationship between alpha-KL and clinical outcome measures was evaluated in uni- and multi-variable models. RESULTS: Median (IQR) alpha-KL was 816 (1020.4) pg/mL and demonstrated a bimodal distribution with two distinct populations, Cohort A [n=97, median alpha-KL 789.3 (767.1)] and Cohort B [n=7, median alpha-KL 4365.1(1374.4), >1.5 IQR greater than Cohort A]. Within Cohort A, ICU non-survivors had significantly higher serum alpha-KL compared to survivors as well as significantly higher APACHE II and SOFA scores, rates of mechanical ventilation, and serum BUN, creatinine, calcium, phosphorus and lactate (all p≤0.05). Serum alpha-KL≥1005, the highest tertile, was an independent predictor of ICU mortality when controlling for co-variates (p=0.028, 95% CI 1.143-11.136). CONCLUSIONS: Elevated serum alpha-KL in patients with septic shock is independently associated with higher mortality. Further studies are needed to corroborate these findings.

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome. METHODS: To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc-) is upregulated in Mecp2-null glia when compared to WT, the role of Xc- in the uptake of NAC and L-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan. RESULTS: We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc- was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc- for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival. CONCLUSIONS: These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.

Development, Implementation, and Evaluation of a Certified Registered Nurse Anesthetist Preceptorship-Mentorship Program.

Little evidence exists to support the effects of a preceptor-mentor program for orienting newly hired certified registered nurse anesthetists (CRNAs). The literature suggests that participation in a preceptorship-mentorship program will increase the satisfaction, confidence, and comfort of both preceptors and newly hired orientees. The purpose of this project was to determine the effects of these outcomes. This program was developed based on best evidence and implemented as a quality improvement project. Three sessions were held to educate preceptors (N = 12) in the following areas: communication skills, providing constructive feedback, and assessing learner's styles and needs. The results suggested that participation significantly increased CRNA preceptor satisfaction and comfort in the precepting experience. The newly hired CRNAs answered that they were mostly or very much satisfied and confident at the completion of their orientation period. This program can be expanded to include additional preceptors and be sustained with future new hires. J Contin Educ Nurs. 2017;48(10):464-473.

Maternal Inflammation Results in Altered Tryptophan Metabolism in Rabbit Placenta and Fetal Brain.

Maternal inflammation has been linked to neurodevelopmental and neuropsychiatric disorders such as cerebral palsy, schizophrenia, and autism. We had previously shown that intrauterine inflammation resulted in a decrease in serotonin, one of the tryptophan metabolites, and a decrease in serotonin fibers in the sensory cortex of newborns in a rabbit model of cerebral palsy. In this study, we hypothesized that maternal inflammation results in alterations in tryptophan pathway enzymes and metabolites in the placenta and fetal brain. We found that intrauterine endotoxin administration at gestational day 28 (G28) resulted in a significant upregulation of indoleamine 2,3-dioxygenase (IDO) in both the placenta and fetal brain at G29 (24 h after treatment). This endotoxin-mediated IDO induction was also associated with intense microglial activation, an increase in interferon gamma expression, and increases in kynurenine and the kynurenine pathway metabolites kynurenine acid and quinolinic acid, as well as a significant decrease in 5-hydroxyindole acetic acid (a precursor of serotonin) levels in the periventricular region of the fetal brain. These results indicate that maternal inflammation shunts tryptophan metabolism away from the serotonin to the kynurenine pathway, which may lead to excitotoxic injury along with impaired development of serotonin-mediated thalamocortical fibers in the newborn brain. These findings provide new targets for prevention and treatment of maternal inflammation-induced fetal and neonatal brain injury leading to neurodevelopmental disorders such as cerebral palsy and autism.

Thermal QST Phenotypes Associated with Response to Lumbar Epidural Steroid Injections: A Pilot Study.

OBJECTIVE: Response to lumbar epidural steroid injection in lumbar radicular pain varies. The purpose of this study is to characterize the changes in quantitative sensory testing (QST) phenotypes of subjects and compare the QST characteristics in patients who do respond to treatment of radicular pain with a lumbar epidural steroid injection (ESI). DESIGN: Prospective, observational pilot study. SETTING: Outpatient pain center. METHODS: Twenty subjects with a lower extremity (LE) radicular pain who were scheduled to have an ESI were recruited. At the visit prior to and four weeks following an ESI, subjects underwent QST measurements of both the affected LE and the contralateral unaffected UE. RESULTS: Following an ESI, nine subjects reported a greater than 30% reduction in radicular pain and 11 reported a less than 30% reduction in radicular pain. Subjects who had less than 30% pain reduction response (nonresponders) to an ESI had increased pre-injection warm sensation threshold (37.30 °C, SD = 2.51 vs 40.39, SD = 3.36, P = 0.03) and heat pain threshold (47.22 °C, SD = 1.38, vs 48.83 °C, SD = 2.10, P = 0.04). Further, the nonresponders also showed increased pre-injection warm sensation threshold as measured in the difference of warm sensation detection threshold difference in the affected limb and the unaffected arm (2.68 °C, SD = 2.92 vs 5.67 °C, SD = 3.22, P = 0.045). Other QST parameters were not affected. CONCLUSIONS: The results show that the nonresponders to ESIs have increased detection threshold to heat pain and warm sensation, suggesting that a preexisting dysfunction in the C fibers in this group of subjects who can be detected by QST. Such altered QST characteristics may prognosticate the response to ESIs.

Ejection time: influence of hemodynamics and site of measurement in the arterial tree.

The left ventricular ejection time is routinely measured from a peripheral arterial waveform. However, the arterial waveform undergoes constant transformation as the pulse wave propagates along the arterial tree. Our goal was to determine if the left ventricular ejection time measured peripherally in the arterial tree accurately reflected the ejection time measured through the aortic valve. Moreover, we examined/accessed the modulating influence of hemodynamics on ejection time measurements. Continuous wave Doppler waveform images through the aortic valve and the simultaneously obtained radial artery pressure waveforms were analyzed to determine central and peripheral ejection times, respectively. The peripheral ejection time was significantly longer than the simultaneously measured central ejection time (174.5±25.2 ms vs. 120.7±14.4 ms; P<0.0001; 17.4±8.7% increase). Moreover, the ejection time prolongation was accentuated at lower blood pressures, lower heart rate and lower pulse wave velocity. The time difference between centrally and peripherally measured ejection times likely reflects intrinsic vascular characteristics. Moreover, given that the ejection time also depends on blood pressure, heart rate and pulse wave velocity, peripherally measured ejection times might need to be adjusted to account for changes in these variables.