Perceptions of stigma associated with chronic knee pain: voices of selected women in Thailand and Malaysia.

INTRODUCTION: A higher prevalence of knee pain in Southeast Asian countries, compared with non-Asian countries, is an established fact. This article hypothesizes that this fact, combined with personal, cultural, and environmental factors, may influence attitudes toward illness and treatment-seeking behavior and adherence. OBJECTIVE: This study aimed to determine current attitudes, stigma, and barriers of women to the management of chronic knee pain and treatment in two Southeast Asian countries. METHODS: Fourteen semi-structured interviews explored female lived perceptions of chronic knee pain in Southeast Asia. Using a phenomenological reduction process, open-ended questions allowed participants to voice their perceptions of their experience of this knee condition. Particular foci were potential stigma associated with the perceptions of others, health-seeking attitudes, and attitudes toward exercise. RESULTS: The shared experiences of managing chronic knee pain revealed the impact of their condition on participants' normality of life and their struggles with pain, limitations, and fear for the future. Key individual, interpersonal, organizational and community barriers and facilitators impacted the health seeking attitudes and engagement with conservative rehabilitation programmes. CONCLUSION: Improved socio-cultural competency and consideration for an individuals' intersectional identity and interpersonal relationships are key to designing rehabilitation and conservative management solutions. Co-creating alternative pathways for rehabilitation for individuals that are more distant from health facilities may help reduce socio-cultural barriers at a community level.

Intraluminal Flow Diverter Design Primer for Neurointerventionalists.

The clinical use of flow diverters for the treatment of intracranial aneurysms has rapidly grown. Consequently, the market and technology for these devices has also grown. Clinical performance characteristics of the flow diverter are well-known to the clinician. However, the engineering design principles behind how these devices achieve ideal clinical performance are less understood. This primer will summarize flow diverter design parameters for neurointerventionalists with the aim of promoting collaboration between clinicians and engineers.

Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets.

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

Does axial cervical pain improve with surgical fusion? A meta-analysis.

OBJECTIVE: Axial neck pain is a prevalent condition that causes significant morbidity and productivity loss. This study aimed to review the current literature and define the impact of surgical intervention on the management of cervical axial neck pain. METHODS: A search was conducted of three databases (Ovid MEDLINE, Embase, and Cochrane) for randomized controlled trials and cohort studies written in the English language with a minimum 6-month follow-up. The analysis was limited to patients with axial neck pain/cervical radiculopathy and preoperative/postoperative Neck Disability Index (NDI) and visual analog scale (VAS) scores. Literature reviews, meta-analyses, systematic reviews, surveys, and case studies were excluded. Two patient groups were analyzed: the arm pain predominant (pAP) cohort and the neck pain predominant (pNP) cohort. The pAP cohort had preoperative VAS neck scores that were lower than the arm scores, whereas the pNP cohort was defined as having preoperative VAS neck scores higher than the arm scores. A 30% reduction in patient-reported outcome measure (PROM) scores from the baseline represented the minimal clinically important difference (MCID). RESULTS: Five studies met the inclusion criteria, involving a total of 5221 patients. Patients with pAP showed a slightly higher percent reduction in PROM scores from baseline than those with pNP. The NDI reduction in patients with pNP was 41.35% (mean change in NDI score 16.3/mean baseline NDI score 39.42) (p < 0.0001), whereas those with pAP had a reduction of 45.12% (15.86/35.15) (p < 0.0001). Surgical improvement was slightly but similarly greater in pNP patients compared with pAP patients (16.3 vs 15.86 points, respectively; p = 0.3193). Regarding VAS scores, patients with pNP had a greater reduction in neck pain, with a change from baseline of 53.4% (3.60/6.74, p < 0.0001), whereas those with pAP had a change from baseline of 50.3% (2.46/4.89, p < 0.0001). The difference in VAS scores for neck pain improvement was significant (3.6 vs 2.46, p < 0.0134). Similarly, patients with pNP had a 43.6% (1.96/4.5) improvement in VAS scores for arm pain (p < 0.0001), whereas those with pAP had 66.12% (4.43/6.7) improvement (p < 0.0001). The VAS scores for arm pain were significantly greater in patients with pAP (4.43 vs 1.96 points, respectively; p < 0.0051). CONCLUSIONS: Overall, despite significant variations in the existing literature, there is mounting evidence that surgical intervention can lead to clinically meaningful improvements in patients with primary axial neck pain. The studies suggest that patients with pNP tend to have better improvement in neck pain than in arm pain. In both groups, the average improvements exceeded the MCID values and reached substantial clinical benefit in all studies. Further research is necessary to identify which patients and underlying pathologies will benefit most from surgical intervention for axial neck pain because it is a multifaceted condition with many causes.

Lumbar Synovial Cysts-Should You Fuse or Not?

BACKGROUND: Spinal synovial cysts are lesions that most commonly occur in the lumbar region. The need for an instrumented spinal fusion in addition to lumbar decompression with removal of the synovial cyst is unknown. OBJECTIVE: To test the hypothesis that select patients who underwent decompression with instrumented fusion for lumbar synovial cysts would be less likely to have subsequent surgery (SS) in a 2-year period than patients treated with laminectomy alone. METHODS: This retrospective cohort study was performed using IBM MarketScan Commercial Claims and Encounters Database. Patients who had a lumbar synovial cyst diagnosis and laminectomy surgery with or without fusion surgery were included in this study. Patients were tracked for SS 2 years after surgery. Laminectomy patients were propensity score-matched to laminectomy with fusion (LF) patients using a 2:1 ratio. The log-rank test and Cox regression were used to compare the cumulative incidence of SS between groups. RESULTS: There were 7664 and 1631 patients treated with laminectomy and LF before matching. After matching, there were 2212 laminectomy and 1631 LF patients and patient characteristics were balanced. The 2-year incidence of recurrent SS was 3.1% ([CI]: 2.2%, 4.0%) and 1.7% (95% CI: 0.9%, 2.5%) laminectomy and LF, respectively. Compared with laminectomy, LF had a statistically significant lower risk of recurrent SS (hazard ratio: 0.56 [95% CI: 0.32-0.97]; P -value: .04). CONCLUSION: All patients who had concomitant lumbar fusion showed decreased chance of having a cyst- or noncyst-related recurrence SS when compared with all patients undergoing laminectomy alone, regardless of diagnosis at the time of SS.

Does Preoperative Opiate Choice Increase Risk of Postoperative Infection and Subsequent Surgery?

BACKGROUND: Opioids are commonly prescribed for chronic pain before spinal surgery and research has shown an increased rate of postoperative adverse events in these patients. OBJECTIVE: This study compared the incidence of 2-year subsequent surgical procedures and postoperative adverse events in patients undergoing lumbar fusion with or without 90-day preoperative opioid use. We hypothesized that patients using preoperative opioids would have a higher incidence of subsequent surgery and adverse outcomes. METHODS: A retrospective cohort study was performed using the Optum Pan-Therapeutic Electronic Health Records database including adult patients who had their first lumbar fusion between 2015 and 2018. The daily average preoperative opioid dosage 90 days before fusion was determined as morphine equivalent dose and further categorized into high dose (morphine equivalent dose >100 mg/day) and low dose (1-100 mg/day). Clinical outcomes were compared after adjusting for confounders. RESULTS: A total of 23,275 patients were included, with 2112 patients (10%) using opioids preoperatively. There was a significantly higher incidence of infection compared with nonusers (12.3% vs. 10.1%; P = 0.01). There was no association between subsequent fusion surgery (7.9% vs. 7.5%; P = 0.52) and subsequent decompression surgery (4.1% vs. 3.6%; P = 0.3) between opioid users and nonusers. Regarding postoperative infection risk, low-dose users showed significantly higher incidence (12.7% vs. 10.1%; P < 0.01), but high-dose users did not show higher incidence than nonusers (7.5% vs. 10.1%; P = 0.23). CONCLUSIONS: Consistent with previous studies, opioid use was significantly associated with a higher incidence of 2-year postoperative infection compared with nonuse. Low-dose opioid users had higher postoperative infection rates than did nonusers.

Preoperative meningioma embolization reduces perioperative blood loss: a multi-center retrospective matched case-control study.

BACKGROUND AND PURPOSE: The utility of preoperative embolization remains controversial within the literature. Here, we evaluate whether preoperative meningioma embolization is effective in reducing intraoperative blood loss, safe to perform, and cost-effective when compared with surgical resection without preoperative embolization. METHODS: Twenty-nine patients with meningiomas were matched by tumor size and location to 29 control patients with meningiomas at another institution where preoperative embolization was not practiced. The variables evaluated were pre- and post-operative hemoglobin and hematocrit levels as a measure of operative blood loss and postoperative morbidity. The additional cost of undergoing angiography and embolization was calculated from hospital charges obtained from the billing department. RESULTS: The mean decrease in perioperative hemoglobin and hematocrit was 0.9 and 2.7, respectively, in the embolization group and 2.8 and 10.0, respectively, in the control group for a significant decrease in operative blood loss as measured by change in hematocrit and hemoglobin levels after surgery. There was no significant difference in operative blood loss when subdividing patients based on tumor location. There were no angiogram-related complications. Twenty-two of 29 patients (76%) underwent embolization of a feeding artery, whereas 7 patients underwent only a diagnostic angiogram. The mean additional charge per patient in the embolization group was $88,767. CONCLUSIONS: Preoperative embolization was safe and effective in reducing the overall perioperative blood loss in patients undergoing meningioma resection, as measured by the change in postoperative hemoglobin and hematocrit levels. However, the cost of embolization was significant.

Hypoglossal nerve injury with C1 lateral mass screw placement: A case report and review of the literature.

We report the case of a 62-year-old man who presented with a progressive myelopathy secondary to spinal cord compression from an odontoid process fracture and subaxial central canal stenosis. The patient underwent a C1-T2 posterior decompression and instrumented fusion (PCDF) and did well immediately postoperatively. However, on POD1, he developed a right hypoglossal nerve (HN) palsy attributed to direct mechanical compression or injury from the C1 lateral mass screw (LMS), which improved following a revision and screw replacement. While HN injury is a known complication of high anterior and anterolateral cervical spine approaches as well as transcondylar screw fixation, this case aims to expand on the limited reports available regarding hypoglossal nerve injury following placement of bicortical C1 LMS. Furthermore, the use of fluoroscopic guidance in addition to anatomic landmarks and triggered electromyography of the tongue are offered as potential solutions to prevent HN injury intraoperatively.

Incidence of Pseudarthrosis and Subsequent Surgery After Cervical Fusion Surgery: A Retrospective Review of a National Health Care Claims Database.

BACKGROUND: Cervical pseudarthrosis is a postoperative adverse event that occurs when a surgically induced fusion fails to establish bone growth connecting the 2 regions. It has both clinical and financial implications and may result in significant patient morbidity; it continues to be one of the leading causes of pain after surgery. METHODS: A retrospective longitudinal cohort study was performed. Patients in the IBM MarketScan Commercial Claims and Encounters (CCAE) database, 18-64 years old, who underwent elective cervical fusions during 2015-2019 were included. Patients with trauma, infection, or neoplasm were excluded. Patients were followed for 2 years from surgical fusion for occurrence of pseudarthrosis. After pseudarthrosis, subsequent surgery was documented, and cumulative incidence curves, adjusted for patient/procedure characteristics, with 95% confidence intervals (CIs) were generated. Risk factors were evaluated with multivariable Cox regression analysis. RESULTS: The cohort included 45,584 patients. The 1-year and 2-year incidence of pseudarthrosis was 2.0% (95% CI, 1.9%-2.2%) and 3.3% (95% CI, 3.1%-3.5%), respectively. Factors significantly associated with increased risk of pseudarthrosis were female gender, current/previous substance abuse, previous spinal pain in the cervical/thoracic/lumbar spine, and Elixhauser score ≥5. Factors significantly associated with decreased risk of pseudarthrosis were anterior cervical approach, use of an interbody cage, and 2-level or 3-level anterior instrumentation. The 1-year and 2-year incidence of subsequent surgery in patients with pseudarthrosis was 11.7% (95% CI, 9.6%-13.7%) and 13.8% (95% CI, 11.5%-16.2%), respectively. CONCLUSIONS: Cervical pseudarthrosis and subsequent surgery still occur at a low rate. Surgical factors such as anterior approach, interbody cage use, and anterior instrumentation may reduce pseudarthrosis risk.

Two classes of functional connectivity in dynamical processes in networks.

The relationship between network structure and dynamics is one of the most extensively investigated problems in the theory of complex systems of recent years. Understanding this relationship is of relevance to a range of disciplines-from neuroscience to geomorphology. A major strategy of investigating this relationship is the quantitative comparison of a representation of network architecture (structural connectivity, SC) with a (network) representation of the dynamics (functional connectivity, FC). Here, we show that one can distinguish two classes of functional connectivity-one based on simultaneous activity (co-activity) of nodes, the other based on sequential activity of nodes. We delineate these two classes in different categories of dynamical processes-excitations, regular and chaotic oscillators-and provide examples for SC/FC correlations of both classes in each of these models. We expand the theoretical view of the SC/FC relationships, with conceptual instances of the SC and the two classes of FC for various application scenarios in geomorphology, ecology, systems biology, neuroscience and socio-ecological systems. Seeing the organisation of dynamical processes in a network either as governed by co-activity or by sequential activity allows us to bring some order in the myriad of observations relating structure and function of complex networks.

Spinal Epidural Abscess Patients Have Higher Modified Frailty Indexes Than Back Pain Patients on Emergency Room Presentation: A Single-Center Retrospective Case-Control Study.

OBJECTIVE: Spinal epidural abscess (SEA) patients have increased medical comorbidities and risk factors for infection compared with those without SEA. However, the association between frailty and SEA patients has not been documented. METHODS: A total of 46 SEA patients were randomly paired and matched by age and sex with a control group of patients with back pain who had presented to our emergency department from 2012 to 2017. Statistical analysis identified the risk factors associated with SEA and frailty using the modified frailty index (mFI), and the patients were stratified into robust, prefrail, and frail groups. We examined the value of the mFI as a prognostic predictor and evaluated the classic risk factors (CRFs). RESULTS: The SEA patients had higher mFIs and CRFs (P = 0.023 and P < 0.001, respectively) and a longer length of stay (22.89 days vs. 1.72 days; P < 0.001). Of the mFI variables, only diabetes had a significant association with SEA (odds ratio [OR], 3.60; P = 0.012). Among the stratified mFI subgroups, a frail ranking (mFI >2) was the strongest risk factor for SEA (OR, 5.18; P = 0.003). A robust ranking (mFI, 0-1) was a weak negative predictor for SEA (OR, 0.41; P = 0.058). The robust patients were also more likely to be discharged to home (OR, 7.58; P = 0.002). Of the CRF variables, only intravenous drug use had a statistically significant association with SEA (OR, 10.72; P = 0.015). CONCLUSIONS: Patients with SEA were more frail compared with the control back pain patients. Frailty was determined to be an independent risk factor for SEA, outside of the CRFs. The use of the mFI could be potentially useful in predicting the diagnosis, prognosticating, and guiding SEA treatment.

Posterior Transdural Approach for a Calcified Thoracic Intradural Disc Herniation Using a 3-Dimensional Exoscope: 2-Dimensional Operative Video.

This video depicts the removal of an intradural thoracic disc herniation through a purely transdural approach. Thoracic disc herniations are rare, and less than 5% are intradural. Though thoracic disc herniations are removed through a posterolateral or transthoracic corridor, there is literature to support a transdural approach for central herniations.1-3 Although the transdural approach has been selectively adopted for central soft herniations, calcified herniations have been regarded as less suitable.1,2 Intradural thoracic herniations have not been specifically addressed by a transdural approach in the limited literature, though it has been utilized in conjunction with a larger transthoracic approach.4 Our case features a 72-yr-old female presenting with worsening left leg weakness. Computed tomography (CT) identified a multilobulated ventral calcified mass at T11-12. Magnetic resonance imaging was not possible because of an incompatible pacemaker. Our impression was that this likely represented an intradural meningioma though a calcified intradural disc herniation was considered. Given the apparent intradural location, we opted for a transdural approach only via T11-12 laminectomy and a midline dural opening. Dentate ligament sectioning allowed a clear corridor to the now apparent disc material. Postoperative CT confirmed near complete resection, and the patient showed neurological improvement. Ultimately, the transdural approach alone led to complete discectomy while avoiding the morbidity of an invasive transthoracic approach and instrumented fusion. To our knowledge, this is the first video documenting a purely transdural approach for resection of an intradural disc herniation. The patient consented to the surgical procedure and to the use of intraoperative video for education purposes.

Longer 6-mm Diameter Stent Retrievers Are Effective for Achieving Higher First Pass Success with Fibrin-Rich Clots.

First pass success (FPS) can be defined as in vitro retrieval of clot in a single pass during mechanical thrombectomy (MT) for acute large vessel occlusion (LVO). Despite advancements in MT technology, retrieval of fibrin-rich clots remains a challenge. Therefore, the effect of stent retriever length on FPS for fibrin-rich clots was investigated by using SolitaireTM 6 × 40 versus 6 × 30 mm devices with a balloon guide catheter (BGC) or distal access catheter (DAC) and sheath, in an in vitro model of anterior circulation neurovascular anatomy. Additionally, vascular safety of the SolitaireTM 6 × 40 versus 6 × 30 mm devices was evaluated in a porcine model for differences in: luminal thrombus, inflammation, endothelial coverage, fibrin deposits, smooth muscle cell loss, elastic lamina and adventitia disruption, intimal hyperplasia, and lumen reduction, at 0, 30, and 90 days post-treatment. In vitro overall FPS was measured as: SolitaireTM 6 × 40 (95%) and SolitaireTM 6 × 30 (67%). FPS for clot location in middle cerebral artery was: (a) BGC (6 × 40 mm: 100%; 6 × 30 mm: 100%; n = 8); (b) DAC with 088 sheath (6 × 40 mm: 83%; 6 × 30 mm: 33%; n = 12). FPS for clot location in internal carotid artery was: (a) BGC (6 × 40 mm: 100%; 6 × 30 mm: 80%; n = 11); (b) DAC with 088 sheath (6 × 40 mm: 100%; 6 × 30 mm: 67%; n = 10). Stent length had a significant effect (Fisher's exact test; p < 0.05) on FPS. In vivo evaluation in the porcine model showed no difference in vascular safety parameters between the SolitaireTM 6 × 40 and 6 × 30 mm devices (p > 0.05) at all time points in the study. Longer stent retrievers may be safe and effective in improving FPS for fibrin-rich clots in in vitro and in vivo models of LVO.

Preclinical safety and efficacy evaluation of the Pipeline Vantage Embolization Device with Shield Technology.

BACKGROUND: The Pipeline Vantage Embolization Device with Shield Technology is a next generation flow diverter developed to improve aneurysm occlusion and implant endothelialization in addition to lowering thrombogenicity. We report here the in vivo biocompatibility and in vitro hemocompatibility performance of the Pipeline Vantage Embolization Device with Shield Technology (Vantage) compared with the Pipeline Flex Embolization Device (Flex). METHODS: Biocompatibility (via histology), aneurysm occlusion and vessel patency (via angiography), and endothelial coverage (via scanning electron microscopy (SEM)) for the Vantage and Flex devices were assessed in the rabbit elastase aneurysm model at 90 days (n=29) and 180 days (n=27). In vitro thrombogenicity for Flex and Vantage (n=16) was assessed using a human blood flow loop model at low heparin concentration (0.6 U/mL) with thrombin generation, platelet activation and thrombus visualization as outputs. RESULTS: Raymond Roy Occlusion Classification grade 1 was higher for Vantage (61%) compared with Flex (46%), but was not statistically significant (p>0.05). All branch vessels were patent. Histological measures for both devices were similar (p>0.05). Endothelial coverage of the implant was significantly better for Vantage compared with Flex (p<0.05). In vitro measurements of thrombin generation (thrombin-antithrombin complex (µg/mL): Vantage 0.49±0.45; Flex 10.57±9.84) and platelet activation (ß-thromboglobulin (IU/µl): Vantage 0.41±0.19; Flex 4.14±2.38) were both statistically lower (p<0.05) for Vantage compared with Flex. High resolution microscopy showed less accumulation of thrombus on Vantage as compared with Flex. CONCLUSION: Vantage improved aneurysm occlusion and implant endothelialization and had significantly lower thrombogenicity as compared with Flex, while preserving the biocompatibility safety profile of Flex.

A new framework for integrated, holistic, and transparent evaluation of inter-basin water transfer schemes.

Water shortages are forecast to affect 50% of the world's population by 2030, impacting developing nations most acutely. To increase water security there has been a significant increase in Inter-basin Water Transfer (IBWT) schemes, engineering mega-projects that redistribute water from one basin to another. However, the implementation of these schemes is often contested, and evaluation of their complex impacts inadequate, or hidden from full public scrutiny. There is an urgent need to develop more integrated, holistic, and transparent ways of evaluating the multiple interlinking impacts of IBWT schemes of this scale. In this paper, we address this gap by outlining an experimental methodology to evaluate IBWT schemes using a multidisciplinary and transparent methodology which utilises publicly available data. We illustrate the method using a case study from the Inter-Linking Rivers Project in Northern India, comparing the results of the experimental approach against the official analysis of the proposed scheme produced by the State Government of Jharkhand. The results demonstrate that the proposed experimental method allows more detailed evaluation of spatial and temporal variability in water availability and demand, as well as holistic evaluation of the functioning of the proposed scheme under different future scenarios. Based on these results we propose a flexible framework for future evaluation of proposed water transfer schemes which embeds the principles of integrated assessment, transparency, and sound science which can be adapted to other IBWT projects across the world.

Retrosigmoid Craniectomy for Resection of Epidermoid causing Trigeminal Neuralgia.

The differential diagnosis for trigeminal neuralgia like-symptoms includes cerebellopontine angle lesions causing regional mass effect upon the trigeminal nerve ( Fig. 1 ). Here we present an operative video manuscript of a patient experiencing trigeminal neuralgia, secondary to an epidermoid cyst, in which a retrosigmoid craniectomy was performed to resect the epidermoid and decompress the trigeminal nerve ( Fig. 2 ). This video highlights the operative nuances to achieving a successful surgery, including appropriate patient positioning, dural exposure to the transverse-sigmoid sinus junction, arachnoid dissection, and decompression of cranial nerves. A gross total resection was achieved; the patient reported immediate relief of facial pain postoperatively and has been pain free at the ten month follow-up. The link to the video can be found at: https://youtu.be/Ja2eE0uGk4E .

Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship.

Activation of Mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerous malignancies including glioblastoma (GB). The Canonical PI3K/Akt/mTOR signaling cascade is commonly upregulated due to loss of the tumor suppressorm PTEN, a phosphatase that acts antagonistically to the kinase (PI3K) in conversion of PIP2 to PIP3. mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling. The main function of mTORC1 is to regulate protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. On the other hand, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK and it also plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. mTORC1 and mTORC2 regulate each other, as shown by the fact that Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, remained ineffective in clinical trials of Glioblastoma (GB) patients, in part due to their incomplete inhibition of mTORC1 as well as unexpected activation of mTOR via the loss of negative feedback loops. In recent years, novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6KSer235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKTSer473. Furthermore by these novel combined mTORC1/mTORC2 inhibitors reduced the proliferation and self-renewal of GB cancer stem cells. However, a search of more effective way to target mTOR has generated a third generation inhibitor of mTOR, "Rapalink", that bivalently combines rapamycin with an ATP-binding inhibitor, which effectively abolishes the mTORC1 activity. All in all, the effectiveness of inhibitors of mTOR complexes can be judged by their ability to suppress both mTORC1/mTORC2 and their ability to impede both cell proliferation and migration along with aberrant metabolic pathways.

Hemodynamic differences between Pipeline and coil-adjunctive intracranial stents.

INTRODUCTION: Modern coil-adjunctive intracranial stent designs have increased metal surface coverage to construct putative 'flow diverter lights.' This is rooted in the assumption that flow diversion is linearly correlated with metal surface coverage rather than being a threshold to be reached by device porosity and design. OBJECTIVE: To evaluate this assumption, by performing computational flow analysis on three aneurysm models treated with low metal surface coverage stents (ATLAS and Enterprise), a Pipeline flow diverter, and the LVIS Blue stent. METHODS: Computational flow analysis was performed on virtual deployment models entailing deployment of an ATLAS, Enterprise, LVIS Blue, or Pipeline. The impact of device deployment on velocity vectors at the neck, maximum wall shear stress, inflow rate into the aneurysm, and turnover time was determined. RESULTS: Velocity vector plots demonstrated low magnitude, localized inflow jets for Pipeline only; asymmetric, selectively high inflow jets were seen for LVIS Blue, and broader velocity vector clusters were seen for Atlas and Enterprise. Reduction in wall shear stress as compared with baseline was significant for all devices and greatest for the Pipeline. Mean peak wall shear stress was significantly lower for LVIS Blue in comparison with ATLAS or Enterprise but significantly lower for Pipeline than for LVIS Blue. Reduction of inflow rate into the aneurysm was significant for LVIS Blue and Pipeline but significantly lower for Pipeline than for LVIS Blue. Turnover time was statistically similar for ATLAS, Enterprise, and LVIS Blue, but significantly increased for Pipeline. CONCLUSION: Considerable differences in peak wall shear stress, inflow rates, and turnover time between flow diverters, moderate- and low-porosity stents reinforce the assumption that effective flow diversion represents a threshold in device design, encompassing metal surface coverage only in part.

Thrombogenicity assessment of Pipeline, Pipeline Shield, Derivo and P64 flow diverters in an in vitro pulsatile flow human blood loop model.

Flow diversion is a disruptive technology for the treatment of intracranial aneurysms. However, these intraluminal devices pose a risk for thromboembolic complications despite dual antiplatelet therapy. We report the thrombogenic potential of the following flow diversion devices measured experimentally in a novel human blood in-vitro pulsatile flow loop model: Pipeline™ Flex Embolization Device (Pipeline), Pipeline™ Flex Embolization Device with Shield Technology™ (Pipeline Shield), Derivo Embolization Device (Derivo), and P64 Flow Modulation Device (P64). Thrombin generation (Mean ±â€¯SD; µg/mL) was measured as: Derivo (28 ±â€¯11), P64 (21 ±â€¯4.5), Pipeline (21 ±â€¯6.2), Pipeline Shield (0.6 ±â€¯0.1) and Negative Control (1.5 ±â€¯1.1). Platelet activation (IU/µL) was measured as: Derivo (4.9 ±â€¯0.7), P64 (5.2 ±â€¯0.7), Pipeline (5.5 ±â€¯0.4), Pipeline Shield (0.3 ±â€¯0.1), and Negative Control (0.9 ±â€¯0.7). We found that Pipeline Shield had significantly lower platelet activation and thrombin generation than the other devices tested (p < .05) and this was comparable to the Negative Control (no device, p > .05). High resolution scanning electron microscopy performed on the intraluminal and cross-sectional surfaces of each device showed the lowest accumulation of platelets and fibrin on Pipeline Shield relative to Derivo, P64, and Pipeline. Derivo and P64 also had higher thrombus accumulation at the flared ends. Pipeline device with Phosphorylcholine surface treatment (Pipeline Shield) could mitigate device material related thromboembolic complications.