Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma.

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.

PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

Connectivity Profile for Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson Disease.

OBJECTIVE: This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial. METHODS: To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]). RESULTS: Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, -13.56, -7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort. INTERPRETATION: These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271-284.

Context-Dependent Glioblastoma-Macrophage/Microglia Symbiosis and Associated Mechanisms.

Glioblastoma (GBM) is a lethal form of primary brain tumor in human adults. The impact of tumor-intrinsic alterations is not exclusively confined to cancer cells but can also be extended to the tumor microenvironment (TME). Glioblastoma-associated macrophages/microglia (GAMs) are a prominent type of immune cells that account for up to 50% of total cells in GBM. Emerging evidence suggests that context-dependent GBM-GAM symbiotic interactions are pivotal for tumor growth and progression. Here, we discuss how specific genetic alterations in GBM cells affect GAM biology and, reciprocally, how GAMs support GBM progression. We hypothesize that understanding context-dependent GBM-GAM symbiosis may reveal the molecular basis of GBM tumorigenesis and lead to novel candidate treatment approaches aiming to improve GBM patient outcomes.

Methods for the induction of labor: efficacy and safety.

This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 µg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease.

OBJECTIVE: The deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5-4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial. MATERIALS AND METHODS: Attempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures. RESULTS: Twelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson's Disease Rating Scale [UPDRS]-IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; pinteraction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire-39 (PDQ-39), and levodopa equivalent daily dose (LEDD). CONCLUSIONS: Eleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016). CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00282152.

Teleneurology via tablet technology: an effective low-cost method to increase healthcare accessibility.

INTRODUCTION: Telemedicine is a valuable tool to increase access to health care, especially for patients in rural areas who need to visit a specialist. In place of telemedicine robots, which are costly and complicated, hospitals have implemented successful telemedicine programs using lower-cost tablet technology; opting for tablet technology increases the organizational feasibility of a large-scale telemedicine program. METHODS: Vanderbilt University Medical Center (VUMC), in Nashville, Tennessee, USA, launched its teleneurology network program in 2014 to serve patients in surrounding community hospitals who needed a neurology consult. Consults are conducted using an iPad, including examinations and the secure sharing of images and patient information. This article reports on teleneurology consult data and the results of patient and physician satisfaction surveys. RESULTS: Between February 2014 and November 2021, the VUMC teleneurology network program provided consultations for 14 241 patients with a wide variety of neurological diagnoses presenting to 12 community-based hospitals. Patient and community physician satisfaction surveys showed that 96% of physicians were satisfied with the overall care provided, and 89% of patients reported that the telehealth visits met their medical needs. CONCLUSION: One of the goals of telemedicine programs is to increase access to care. Therefore, it is important that the technology used to implement the program also be accessible in terms of cost and complexity. Tablets are low-cost technology, and their use in telemedicine has been shown to satisfy both physicians and patients with a wide variety of diagnoses.

Real-world efficacy of treatment with benralizumab, dupilumab, mepolizumab and reslizumab for severe asthma: A systematic review and meta-analysis.

BACKGROUND: Severe asthma is a major cause of morbidity. Some patients may benefit from biological therapies. Most evaluations of these treatments are derived from randomized controlled trials (RCTs), but few patients are eligible for these trials. Studies involving more diverse groups of participants exist, but there is a lack of precise pooled estimates. OBJECTIVE: This systematic review aims to evaluate the real-world efficacy of recently and nearly licensed biological therapies for severe asthma to assess the generalizability of the RCT data. METHODS: Clinical outcomes including exacerbation rate, oral corticosteroid usage, forced expiratory volume in 1 second (FEV1 ) and fractional exhaled nitric oxide (FeNO) were examined. Studies were assessed for risk of bias using the Critical Appraisal Skills Programme checklist tool. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: A total of 21 studies examining biologicals in real-world settings were identified; they mostly focused on benralizumab and mepolizumab. The introduction of biologicals reduced the annualzsed exacerbation rate significantly by -3.79 (95% confidence interval [CI] -4.53, -3.04), -3.17 (95% CI -3.74, -2.59) and -6.72 (95% CI -8.47, -4.97) with benralizumab, mepolizumab and reslizumab, respectively. Likewise, improvements were observed in FEV1 (0.17 L 95% CI 0.11, 0.24) and FeNO (-14.23 ppb 95% CI -19.71, -8.75) following the treatment with mepolizumab. After treatment with benralizumab, there was an increase in FEV1 (0.21 L 95% CI 0.08, 0.34). CONCLUSIONS: These data demonstrate that anti-IL5 biologicals may improve the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs. The data were mainly retrospective and unadjusted, so estimated effect sizes may not be reliable. More data are needed to acquire accurate effect estimates in different subpopulations of patients.

Identifying Benefits, Challenges, and Options for Improvement of Veterinary Work-Based Learning in Bangladesh.

Work-based learning (WBL) provides relevant contemporary experience of working environments. Potential benefits for students include developing invaluable skills (clinical, personal, cultural, and professional) and gaining greater awareness of the profession and future career opportunities. However, there are also challenges related to running and sustaining a successful WBL program. In the context of this study, WBL refers to external placements undertaken by final-year students. The aims of the study were to identify ways to optimize the benefits while managing the challenges in delivering WBL in a veterinary curriculum. An in-depth study was undertaken at Chattogram Veterinary and Animal Sciences University (CVASU), Bangladesh, where a WBL program has been in place for 20 years. Final-year veterinary students at CVASU were surveyed to ascertain WBL experiences; survey findings were further explored in focus groups with students, recent graduates, faculty, and placement providers. Most agreed that they had sufficient opportunities to observe, assist, and directly handle pet and farm animals with top skills learned, including clinical diagnosis and communication, and recognized the value of learning in professional workplaces. Based on suggested areas of improvement, the following recommendations can be made: carefully selecting placements, adjusting time allocation, improving communication and building strong collaborations with placement providers, allowing students to customize more placements to align with their career preferences, and staffing adequately to arrange placements and manage a WBL program. Overall, results suggest the current WBL arrangements at CVASU are reasonably good, but there are some specific areas for improvement.

Is a 50% improvement threshold adequate to justify progression from sacral neuromodulation testing to implant?

PURPOSE: A ≥50% subjective improvement in urinary symptoms during sacral neuromodulation testing (SNM-I) is currently used as the indication for progression to second-stage implantation (SNM-II). While most patients will have successful SNM-I and proceed to SNM-II, deterioration in efficacy over time has been reported. It remains unclear if the durability of efficacy is related to the initial symptom reduction. We sought to determine if the degree of improvement after SNM-I is sufficient to predict long-term success. METHODS: The records of all patients who underwent sacral neuromodulation (SNM) for overactive bladder were reviewed. Subjects were divided into those who reported 50%-75% improvement (Group 1) and more than 75% improvement (Group 2) after SNM-I. Differences in clinical variables and long-term device efficacy were compared between groups. RESULTS: Of 213 patients who underwent SNM-I, 137 underwent permanent device implantation. A total of 76 (55%) and 61 (45%) patients reported 50%-75% (Group 1) and more than 75% (Group 2) symptomatic improvement, respectively. With a mean follow-up of 46 months, 44% of Group 1 patients and 68% of Group 2 patients still had a functioning device providing the symptomatic benefit (p = 0.007). Univariate analyses identified the presence of stress urinary incontinence at baseline and having a more than 75% improvement after SNM-I as predictors of long-term functional success. CONCLUSIONS: Compared to patients reporting 50%-75% symptomatic reduction after SNM-I, individuals with a more than 75% improvement during SNM-I were more likely to maintain device efficacy over time. Additional study is warranted to determine if the improvement threshold for progression to SNM-II should be increased.

Factors associated with recurrent urinary tract infections in spinal cord injured patients who use intermittent catheterization.

INTRODUCTION: Urinary Tract Infection (UTI) has been cited as the primary cause of morbidity in patients with history of spinal cord injury (SCI). Despite the significance of recurrent UTI (rUTI) in this population, the causative physiologic and patient characteristics are not well described. We sought to assess associations between demographic, clinical and urodynamic variables and rUTI. MATERIALS AND METHODS: The records of 136 individuals with SCI who perform clean intermittent catheterization (CIC) were retrospectively reviewed. All had a video urodynamics study (VUDS) available for analysis. Individuals were divided into non-recurrent (< 3/year) or rUTI (≥ 3/year) groups. Differences between the cohorts were analyzed. Multivariable logistic regression was performed to determine associations between various demographic, clinical, and VUDS variables and rUTI. RESULTS: Self-reported rUTI were noted in 58 of 136 individuals. Of 124 individuals with urinary culture results, African American race (43.3% vs. 22.3%) and 'Other' race (13.3% vs. 8.5%) made up larger proportions in the rUTI group. Female gender (OR 4.96, 95% CI [1.44-17.13]) and African American race (OR 5.16, 95% CI [1.80-14.79]) were increasingly associated with rUTI on multivariable logistic regression. Shorter interval since injury was also significantly associated with recurrent infections with each year since injury indicating diminished likelihood (OR 0.91, 95% CI [0.82-0.99]). There were no significant differences in VUDS variables between groups and none were significant on regression as potential determinants of rUTI. CONCLUSIONS: Patient race, gender, and time since SCI appear to have significant associations with rUTI in individuals with SCI using CIC. However, VUDS variables were not found to be significantly associated with rUTI.

Vanderbilt University Medical Center Ambulatory Teleneurology COVID-19 Experience.

Background: Telehealth has proliferated since the 1950s, but adoption and coverage of telehealth services for the U.S. public have been slow. In response to the coronavirus disease 2019 (COVID-19) pandemic, the federal government has implemented temporary policy changes that removed barriers and catalyzed the unprecedented adoption of telehealth. Methods: To assess ambulatory teleneurology satisfaction, we analyzed postvisit questionnaire data from patients and clinicians who completed teleneurology visits during the COVID-19 pandemic at Vanderbilt University Medical Center Department of Neurology (VUMC). Results: From March 18 to May 8, 2020, VUMC completed 3,935 teleneurology visits. More than 97% of patients were very highly or highly confident in the telehealth care they received, whereas almost 99% of clinicians were very likely or somewhat likely to recommend telehealth to other clinicians. Conclusions: Teleneurology satisfaction at VUMC has been positive, and going forward, we must advance upon this unprecedented adoption of telehealth and never revert to former restrictive policies.

A surveillance method to identify patients with sepsis from electronic health records in Hong Kong: a single centre retrospective study.

BACKGROUND: Currently there are only two population studies on sepsis incidence in Asia. The burden of sepsis in Hong Kong is unknown. We developed a sepsis surveillance method to estimate sepsis incidence from a population electronic health record (EHR) in Hong Kong using objective clinical data. The study objective was to assess our method's performance in identifying sepsis using a retrospective cohort. We compared its accuracy to administrative sepsis surveillance methods such as Angus' and Martin's methods. METHOD: In this single centre retrospective study we applied our sepsis surveillance method on adult patients admitted to a tertiary hospital in Hong Kong. Two clinicians independently reviewed the clinical notes to determine which patients had sepsis. Performance was assessed by sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) of Angus', Martin's and our surveillance methods using clinical review as "gold standard." RESULTS: Between January 1 and February 28, 2018, our sepsis surveillance method identified 1352 adult patients hospitalised with suspected infection. We found that 38.9% (95%CI 36.3-41.5) of these patients had sepsis. Using a 490 patient validation cohort, two clinicians had good agreement with weighted kappa of 0.75 (95% CI 0.69-0.81) before coming to consensus on diagnosis of uncomplicated infection or sepsis for all patients. Our method had sensitivity 0.93 (95%CI 0.89-0.96), specificity 0.86 (95%CI 0.82-0.90) and an AUC 0.90 (95%CI 0.87-0.92) when validated against clinician review. In contrast, Angus' and Martin's methods had AUCs 0.56 (95%CI 0.53-0.58) and 0.56 (95%CI 0.52-0.59), respectively. CONCLUSIONS: A sepsis surveillance method based on objective data from a population EHR in Hong Kong was more accurate than administrative methods. It may be used to estimate sepsis population incidence and outcomes in Hong Kong. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov on October 3, 2019 ( NCT04114214 ).

Dual bioluminescence and near-infrared fluorescence monitoring to evaluate spherical nucleic acid nanoconjugate activity in vivo.

RNA interference (RNAi)-based gene regulation platforms have shown promise as a novel class of therapeutics for the precision treatment of cancer. Techniques in preclinical evaluation of RNAi-based nanoconjugates have yet to allow for optimization of their gene regulatory activity. We have developed spherical nucleic acids (SNAs) as a blood-brain barrier-/blood-tumor barrier-penetrating nanoconjugate to deliver small interfering (si) and micro (mi)RNAs to intracranial glioblastoma (GBM) tumor sites. To identify high-activity SNA conjugates and to determine optimal SNA treatment regimens, we developed a reporter xenograft model to evaluate SNA efficacy in vivo. Engrafted tumors stably coexpress optical reporters for luciferase and a near-infrared (NIR) fluorescent protein (iRFP670), with the latter fused to the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT). Using noninvasive imaging of animal subjects bearing reporter-modified intracranial xenografts, we quantitatively assessed MGMT knockdown by SNAs composed of MGMT-targeting siRNA duplexes (siMGMT-SNAs). We show that systemic administration of siMGMT-SNAs via single tail vein injection is capable of robust intratumoral MGMT protein knockdown in vivo, with persistent and SNA dose-dependent MGMT silencing confirmed by Western blotting of tumor tissue ex vivo. Analyses of SNA biodistribution and pharmacokinetics revealed rapid intratumoral uptake and significant intratumoral retention that increased the antitumor activity of coadministered temozolomide (TMZ). Our study demonstrates that dual noninvasive bioluminescence and NIR fluorescence imaging of cancer xenograft models represents a powerful in vivo strategy to identify RNAi-based nanotherapeutics with potent gene silencing activity and will inform additional preclinical and clinical investigations of these constructs.

Prevalence of Comorbid Spasticity and Urinary Incontinence in Residents of a Long-Term Care Facility.

The current study evaluated the prevalence of comorbid spasticity and urinary incontinence (UI) in a long-term care facility. Medical history, presence of UI, and activities of daily living (ADL) dependency were obtained from medical records and Minimum Data Set 3.0. Quality of life was assessed with the EuroQoL-5D-5L (EQ-5D). Comorbid spasticity and UI presented in 29% of participants (14 of 49). Participants with spasticity and UI had higher ADL dependency and lower EQ-5D than participants without both conditions (4.9, 95% confidence interval [CI] [1.6, 80.], p = 0.003; -0.17, 95% CI [-0.33, 0.00], p = 0.044; respectively). More than one half of participants with lower limb spasticity had severe UI, compared to only 10% without lower limb spasticity (relative risk = 5.5; 95% CI [1.9, 15.9]; p = 0.006). Comorbid spasticity and UI may be common in the long-term care setting and negatively associated with ADL and quality of life. Further investigation is needed to confirm these findings. [Journal of Gerontological Nursing, 46(10), 35-42.].

Persistent gamma delta T-cell dysfunction in chronic HCV infection despite direct-acting antiviral therapy induced cure.

Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRVγ9Vδ2 T-cell dysfunction in treated HCV patients however is not well studied and was the subject of this investigation. Peripheral blood cells from patients who had achieved sustained virologic response (SVR) or those who had relapsed after interferon-free therapy were phenotyped using flow cytometry. Functional potential of Vγ9Vδ2 T cells was tested by measuring proliferation in response to aminobisphosphonate zoledronic acid, and cytotoxicity against HepG2 hepatoma cell line. TCR sequencing was performed to analyse impact of HCV infection on Vδ2 T-cell repertoire. Vγ9Vδ2 cells from patients were activated and therapy resulted in reduction of CD38 expression on these cells in SVR group. Relapsed patients had Vδ2 cells with persistently activated and terminally differentiated cytotoxic phenotype (CD38+ CD45RA+ CD27- CD107a+ ). Irrespective of outcome with therapy, majority of patients had persistently poor Vδ2 T-cell proliferative response to zoledronate along with lower expression of CD56, which identifies anti-tumour cytotoxic subset, relative to healthy controls. There was no association between the number of antigen reactive Vγ2-Jγ1.2 TCR rearrangements at baseline and levels of proliferation indicating nonresponse to zoledronate is not due to depletion of phosphoantigen responding chains. Thus, HCV infection results in circulating Vγ9Vδ2 T cells with a phenotype equipped for immediate effector function but poor cytokine response and expansion in response to antigen, a functional defect that may have implications for susceptibility for carcinogenesis despite HCV cure.

Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod.

INTRODUCTION: Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15-20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients. METHODS: Pre-treatment and on-treatment α-[11C]-methyl-L-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ. RESULTS: Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment. CONCLUSIONS: Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.

Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators.

BACKGROUND: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs). METHODS: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 µM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s <800 nM) and improved CNS penetration (rat Kp >2, an ~100-fold increase). RESULTS: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs. CONCLUSION: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.

Teleneurology service provided via tablet technology: 3-year outcomes and physician satisfaction.

INTRODUCTION: This study aimed to demonstrate that teleneurology consultations conducted via tablet technology are an efficient and cost-effective means of managing acute neurologic emergencies at community-based hospitals and that utilizing such technology yields high community physician satisfaction. METHOD: During a 39-month period, Vanderbilt University Medical Center in Tennessee USA, provided teleneurology services to 10 community-based hospitals that lacked adequate neurology coverage. Hospitalists at one community-based hospital were not comfortable treating any patient with a neurologic symptom, resulting in 100% of those patients being transferred. This facility now retains more than 60% of neurology patients. For less than US$1200, these hospitals were able to meet the only capital expenditure required to launch this service: the purchase of handheld tablet computers. Real-time teleneurology consultations were conducted via tablet using two-way video conferencing, radiologic image sharing, and medical record documentation. Community physicians were regularly surveyed to assess satisfaction. RESULTS: From February 2014 to May 2017, 3626 teleneurology consultations were conducted. Community physicians, in partnership with neurologists, successfully managed 87% of patients at the community-based hospital. Only 13% of patients required transfer to another facility for a higher level of care. The most common diagnoses included stroke (34%), seizure (11%), and headache/migraine (6%). The average time for the neurologist to answer a request for consultation page and connect with the community physician was 10.6 minutes. Ninety-one percent of community physicians were satisfied or somewhat satisfied with the overall service. CONCLUSION: In the assessment of neurology patients, tablets are a more cost-effective alternative to traditional telehealth technologies. The devices promote efficiency in consultations through ease of use and low transfer rates, and survey results indicate community physician satisfaction.

An overview of meningiomas.

Meningiomas are the most common primary intracranial tumor. Important advances are occurring in meningioma research. These are expected to accelerate, potentially leading to impactful changes on the management of meningiomas in the near and medium term. This review will cover the histo- and molecular pathology of meningiomas, including recent 2016 updates to the WHO classification of CNS tumors. We will discuss clinical and radiographic presentation and therapeutic management. Surgery and radiotherapy, the two longstanding primary therapeutic modalities, will be discussed at length. In addition, data from prior and ongoing investigations of other treatment modalities, including systemic and targeted therapies, will be covered. This review will quickly update the reader on the contemporary management and future directions in meningiomas. [Formula: see text].