UW Neurological Surgery Recent PubMed Publications

Neuroticism may not reflect emotional variability.

Proc Natl Acad Sci U S A. 2020 04 28;117(17):9270-9276

Authors: Kalokerinos EK, Murphy SC, Koval P, Bailen NH, Crombez G, Hollenstein T, Gleeson J, Thompson RJ, Van Ryckeghem DML, Kuppens P, Bastian B

Abstract
Neuroticism is one of the major traits describing human personality, and a predictor of mental and physical disorders with profound public health significance. Individual differences in emotional variability are thought to reflect the core of neuroticism. However, the empirical relation between emotional variability and neuroticism may be partially the result of a measurement artifact reflecting neuroticism's relation with higher mean levels-rather than greater variability-of negative emotion. When emotional intensity is measured using bounded scales, there is a dependency between variability and mean levels: at low (or high) intensity, it is impossible to demonstrate high variability. As neuroticism is positively associated with mean levels of negative emotion, this may account for the relation between neuroticism and emotional variability. In a metaanalysis of 11 studies (N = 1,205 participants; 83,411 observations), we tested whether the association between neuroticism and negative emotional variability was clouded by a dependency between variability and the mean. We found a medium-sized positive association between neuroticism and negative emotional variability, but, when using a relative variability index to correct for mean negative emotion, this association disappeared. This indicated that neuroticism was associated with experiencing more intense, but not more variable, negative emotions. Our findings call into question theory, measurement scales, and data suggesting that emotional variability is central to neuroticism. In doing so, they provide a revisionary perspective for understanding how this individual difference may predispose to mental and physical disorders.

PMID: 32295883 [PubMed - indexed for MEDLINE]

Anterior Column Realignment: Analysis of Neurological Risk and Radiographic Outcomes.

Neurosurgery. 2020 09 01;87(3):E347-E354

Authors: Saigal R, Akbarnia BA, Eastlack RK, Bagheri A, Tran S, Brown D, Bagheri R, Mundis GM

Abstract
BACKGROUND: Anterior column realignment (ACR) is a less invasive alternative to 3-column osteotomy for the correction of sagittal imbalance. We hypothesized that ACR would correct sagittal imbalance with an acceptable neurological risk.
OBJECTIVE: To assess long-term neurological and radiographic outcomes after ACR.
METHODS: Patients ≥18 yr who underwent ACR from 2005 to 2013 were eligible. Standing scoliosis radiographs were studied at preoperation, postoperation (≤6 wk), and at minimum 2 yr of follow-up. Clinical/radiographic data were collected through a retrospective chart review, with thoracic 1 spino-pelvic inclination (T1SPi) used as the angular surrogate for sagittal vertical axis.
RESULTS: A total of 26 patients had complete data, with a mean follow-up of 2.8 yr (1.8-7.4). Preoperative, sagittal parameters were lumbar lordosis (LL) of -16.1°, pelvic incidence (PI)-LL of 41.7°, T1SPi of 3.6°, and pelvis tilt (PT) of 32.4°. LL improved by 30.6° (P < .001) postoperation. Mean changes in PT (-8.3), sacral slope (8.9), T1SPi (-4.9), and PI-LL (-33.5) were all significant. The motion segment angle improved by 26.6°, from 5.2° to -21.4° (P < .001). Neurological complications occurred in 32% patients postoperation (n = 8; 1 patient with both sensory and motor). New thigh numbness/paresthesia developed in 3 (13%) patients postoperation; only 1 (4%) persisted at latest follow-up. A total of 6 (24%) patients developed a new lower extremity motor deficit postoperation, with 4 (8%) having persistent new weakness at last follow-up. Out of 8 patients with preoperative motor deficit, half saw improvement postoperation and 75% improved by last follow-up.
CONCLUSION: There was net motor improvement, with 24% of patients improving and 16% having persistent new weakness at latest follow-up; 60% were unchanged. Radiographic results demonstrate that ACR is a useful tool to treat severe sagittal plane deformity.

PMID: 32297951 [PubMed - indexed for MEDLINE]

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

Ann Clin Transl Neurol. 2020 Apr 15;:

Authors: Kaley TJ, Panageas KS, Pentsova EI, Mellinghoff IK, Nolan C, Gavrilovic I, DeAngelis LM, Abrey LE, Holland EC, Omuro A, Lacouture ME, Ludwig E, Lassman AB

Abstract
PURPOSE: Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose.
METHODS: Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg.
RESULTS: We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1).
CONCLUSION: Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

PMID: 32293798 [PubMed - as supplied by publisher]

Investigating the Suitability of Semicarbazide as an Indicator of Preharvest Nitrofurazone Use in Raw Chicken.

J Food Prot. 2020 Aug 01;83(8):1368-1373

Authors: Johnston J, Duverna R, Williams M, Kishore R, Yee C, Jarosh J

Abstract
ABSTRACT: Semicarbazide (SEM) is the U.S. Food and Drug Administration's official marker for nitrofurazone use in food animals. The U.S. Department of Agriculture Food Safety and Inspection Service conducted a study to evaluate the source of SEM that was identified by a U.S. trading partner in a subset of chicken samples presented for inspection, even though nitrofurazone has been banned from use in U.S. food-producing animals since 2002. The study design included analyses to detect and quantify total and bound SEM in chicken collected from the eight U.S. establishments that were associated with the reported detection of SEM. Samples were collected immediately following evisceration, chilling, and cutting carcass into parts (cut-up). Although antimicrobial interventions (processes to reduce pathogen concentrations) are typically used at all three of these processing steps, the product contact time during chilling is significantly longer (hours versus seconds) than during evisceration and cut-up. In addition, parts were analyzed after 0, 10, 20, and 30 days of frozen storage. No postevisceration samples tested positive for SEM; however, most samples collected postchilling and after cut-up tested positive. The absence of SEM in postevisceration samples and detection in the subsequent postchilling samples and after the cut-up samples suggest that the detection of SEM in the sampled products is not indicative of preharvest nitrofurazone use and may be a result of postharvest processing in these establishments.
HIGHLIGHTS:

PMID: 32294171 [PubMed - indexed for MEDLINE]

The Endoscopic Trans-Superior Articular Process Approach: A Novel Minimally Invasive Surgical Corridor to the Lateral Recess.

Oper Neurosurg (Hagerstown). 2020 Apr 13;:

Authors: Hasan S, White-Dzuro B, Barber JK, Wagner R, Hofstetter CP

Abstract
BACKGROUND: Transforaminal approaches to the lumbar spine are typically performed utilizing Kambin's triangle as approach corridor; however, degenerative changes can distort anatomy and expose the exiting nerve root to inadvertent injury.
OBJECTIVE: To describe the surgical technique of a novel full-endoscopic approach to access the lateral recess and report clinical outcomes.
METHODS: The trans-superior articular process (SAP) approach involves partial resection of the SAP, allowing access to the lateral recess both ventral and dorsal to the traversing nerve root. A retrospective review of 40 patients who had undergone a trans-SAP approach for decompression of lateral recess pathology was conducted. Outcomes were measured using visual analog scores (VAS) and Oswestry Disability Index (ODI) at 2 wk, 3 mo, and at last follow-up.
RESULTS: At a mean follow-up of 24 mo, patients experienced statistically significant improvement of the VAS for ipsilateral leg pain, VAS for back pain, and ODI when comparing preoperative values to all postoperative time points. The percentage of patients reaching a minimally clinically important difference for VAS leg pain and ODI was approximately 90% and 88%, respectively. The complication profile was favorable with no dural tears and no postoperative motor or sensory deficits. One patient required revision, with a total reoperation rate of 3%.
CONCLUSION: The trans-SAP approach is a novel approach that utilizes a safe surgical corridor via the SAP to access lateral recess pathology. Our initial clinical experience suggests that the trans-SAP approach allows for treatment of lateral recess and foraminal pathology with low complication rates.

PMID: 32281629 [PubMed - as supplied by publisher]

Timing of Ossification of the Anterior Skull Base in Syndromic Synostosis.

J Craniofac Surg. 2020 Jul-Aug;31(5):1256-1260

Authors: Nassar AH, Mercan E, Massenburg BB, Lee A, Brown J, Skladman R, Guo Y, Hopper RA

Abstract
The anterior skull base undergoes a progressive ossification after birth. This has implications on the epidural dissection of early trans-craniofacial osteotomy procedures such as monobloc advancements. Our purpose was to determine the rate of ossification in syndromic synostosis patients relative to a normal cohort to establish when maturation of the anterior skull base is complete. The authors analyzed CT scans from 35 patients with Crouzon, Apert or Pfeiffer syndrome, and 84 patients without any craniofacial anomaly between the ages of 0 and 6 years. The non-ossified anterior skull base area was measured using 3D Slicer. The authors compared the sizes of the defects at different ages between the three syndromes and with the control group using Mann-Whitney test. Significance was set at P < 0.05. All patients less than 12 months of age had a measurable defect anterior to the cribriform whereas patients greater than five years of age had full ossification of the anterior skull base with no evidence of defect. The relationship of defect size and age at scan was non-linear, with most defects closing rapidly in the first six months. The temporal closure pattern of the defect was similar between the three syndromes and the control group with no significant difference. Our findings indicate that syndromic children undergo skull base maturation at the same rate as non-syndromic cases, with the majority ossified by three years of age. Anterior skull base surgeries performed before three years should optimize visualization of this area during dissection.

PMID: 32282683 [PubMed - indexed for MEDLINE]

The Cognitive Effects of Statins are Modified by Age.

Sci Rep. 2020 04 10;10(1):6187

Authors: Alsehli AM, Olivo G, Clemensson LE, Williams MJ, Schiöth HB

Abstract
To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

PMID: 32277109 [PubMed - indexed for MEDLINE]

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-mesothelin (CRS-207) With or Without Nivolumab in Patients with Pancreatic Cancer.

Clin Cancer Res. 2020 Apr 09;:

Authors: Tsujikawa T, Crocenzi T, Durham JN, Sugar EA, Wu AA, Onners B, Nauroth JM, Anders RA, Fertig EJ, Laheru DA, Reiss K, Vonderheide RH, Ko AH, Tempero MA, Fisher GA, Considine M, Danilova L, Brockstedt DG, Coussens LM, Jaffee EM, Le DT

Abstract
PURPOSE: Two studies in previously-treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).
EXPERIMENTAL DESIGN: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses and immunologic correlates.
RESULTS: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 (95% CI, 4.7, 8.6) and 6.1 (95% CI, 3.5, 7.0) months, respectively, with a hazard ratio 0.86 (95% CI, 0.55, 1.34). Objective responses were seen in three patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The <underline>><underline> grade 3 related adverse event rate while higher in Arm A (35.3% vs 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only.
CONCLUSIONS: While the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable to standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.

PMID: 32273276 [PubMed - as supplied by publisher]

High frequency nonlinear Doppler contrast-enhanced ultrasound imaging of blood flow.

IEEE Trans Ultrason Ferroelectr Freq Control. 2020 Apr 08;:

Authors: Bruce M, Hannah A, Hammond R, Khaing ZZ, Tremblay-Darveau C, Burns PN, Hofstetter CP

Abstract
Current methods for in-vivo microvascular imaging (<1mm) are limited by trade-offs between depth of penetration, resolution and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (>7.5MHz) are able to visualize smaller vasculature, however are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due inpart to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with non-linear Doppler processing of ultrasound contrast agents at 15MHz to improve resolution of microvascular blood flow, while compensating for reduced microbubble response. This planewave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the non-linear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring sub-millimeter resolution.

PMID: 32275589 [PubMed - as supplied by publisher]

Sustained release of stromal cell-derived factor-1 alpha from silk fibroin microfiber promotes urethral reconstruction in rabbits.

J Biomed Mater Res A. 2020 Apr 10;:

Authors: Liu Y, Huang L, Yuan W, Zhang D, Gu Y, Huang J, Murphy S, Ali M, Zhang Y, Song L

Abstract
We developed a stromal cell-derived factor-1 alpha (SDF-1α)-aligned silk fibroin (SF)/three-dimensional porous bladder acellular matrix graft (3D-BAMG) composite scaffold for long-section ventral urethral regeneration and repair in vivo. SDF-1α-aligned SF microfiber/3D-BAMG, aligned SF microfiber/3D-BAMG, and nonaligned SF microfiber/3D-BAMG scaffolds were prepared using electrostatic spinning and wet processing. Adipose-derived stem cell (ADSC) and bone marrow stromal cell (BMSC) migration was assessed in the SDF-1α-loaded scaffolds. Sustained SDF-1α release in vitro and vivo was analyzed using enzyme-linked immunosorbent assay (ELISA) and western blotting, respectively. The scaffolds were used to repair a 1.5 × 1 cm2 ventral urethral defect in male rabbits in vivo. General observation and retrograde urinary tract contrast assessment were used to examine urethral lumen patency and continuity at 1 month and 3 months post-surgery. Postoperative rehabilitation was evaluated using histological detection. The composite scaffolds sustained SDF-1α release for over 16 days in vitro. SDF-1α-aligned SF nanofiber promoted regeneration of urethral mucosa, submucosal smooth muscles, and microvasculature, increased cellular proliferation, and reduced collagen deposition. SDF-1α expression was increased in reconstructed urethra at 3 months post-surgery in SDF-1α-aligned SF group. SDF-1α-aligned SF microfiber/3D-BAMG scaffolds may be used to repair and reconstruct long urethral defects because they accelerate urethral regeneration.

PMID: 32276293 [PubMed - as supplied by publisher]

Ghost Aneurysms in Acute Subdural Hematomas: A Report of Two Cases.

World Neurosurg. 2020 07;139:e159-e165

Authors: Abecassis ZA, Nistal DA, Abecassis IJ, Sen RD, Levitt MR

Abstract
OBJECTIVE: Acute subdural hematoma (aSDH) is a common pathology encountered in neurosurgery. Although most cases are associated with trauma and injuries to draining veins, traumatic aSDH from injury to arteries or spontaneous aSDH because of a ruptured intracranial aneurysm can occur. For some patients without a clear clinical history, it can be difficult to distinguish between these etiologies purely based on radiography. The objective of this research was to describe a case series in which imaging was suggestive of the presence of distal cortical intracranial aneurysm associated with aSDH, but operative management demonstrated no evidence of aneurysm.
METHODS: We retrospectively reviewed 2 patients known to have aSDH with suspicion for associated aneurysm between May 2019 and September 2019 at our institution. Data collected included demographic, clinical, and operative course, including age, gender, past medical history, presenting symptoms, and pre and postoperative imaging.
RESULTS: In 2 patients presenting with aSDH with preoperative radiographic imaging suggesting distal middle cerebral artery aneurysms, surgical exploration revealed no aneurysm. In both cases, noniatrogenic active arterial bleeding from an injured cortical middle cerebral artery branch was identified.
CONCLUSIONS: Although there are prior reports of arterial aSDH, to our knowledge, this is the first to describe the radiographic "ghost aneurysm" sign. It is important for clinicians to be aware of this potential misleading radiographic sign, which indicates active extravasation into a spherical cast of clot.

PMID: 32272269 [PubMed - indexed for MEDLINE]

Patterns of Failure After Stereotactic Radiosurgery for Recurrent High-Grade Glioma: A Single Institution Experience of 10 Years.

Neurosurgery. 2019 08 01;85(2):E322-E331

Authors: Ene CI, Macomber MW, Barber JK, Ferreira MJ, Ellenbogen RG, Holland EC, Rockhill JK, Silbergeld DL, Halasz LM

Abstract
BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit.
OBJECTIVE: To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas.
METHODS: We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line.
RESULTS: Most patients with recurrent HGG developed "in-field" treatment failure following SRS (n = 40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio = 0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P = .016). There was a statistically significant increase in distant versus in-field failure among older patients (P = .035). This effect was independent of bevacizumab use (odds ratio = 0.54, P = 1.0).
CONCLUSION: Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.

PMID: 30576476 [PubMed - indexed for MEDLINE]

Both Dietary Ratio of n-6 to n-3 Fatty Acids and Total Dietary Lipid Are Positively Associated with Adiposity and Reproductive Health in Zebrafish.

Curr Dev Nutr. 2020 Apr;4(4):nzaa034

Authors: Fowler LA, Dennis-Cornelius LN, Dawson JA, Barry RJ, Davis JL, Powell ML, Yuan Y, Williams MB, Makowsky R, D'Abramo LR, Watts SA

Abstract
Background: Controversial findings have been reported in human and animal studies regarding the influence of n-6 (ω-6) to n-3 (ω-3) fatty acid ratios on obesity and health. Two confounding factors may be related to interactions with other dietary lipid components or sex-specific differences in fatty acid metabolism.
Objective: This study investigated main and interactive effects of total dietary lipid, ratio of n-6 to n-3 fatty acids, and sex on growth, adiposity, and reproductive health in wild-type zebrafish.
Methods: Male and female zebrafish (3 wk old) were fed 9 diets consisting of 3 ratios of n-6 to n-3 fatty acids (1.4:1, 5:1, and 9.5:1) varied within 3 total lipid amounts (80, 110, and 140 g/kg) for 16 wk. Data were then collected on growth, body composition (determined by chemical carcass analysis), and female reproductive success (n = 32 breeding events/diet over 4 wk). Main and interactive effects of dietary lipid and sex were evaluated with regression methods. Significant differences within each dietary lipid component were relative to the intercept/reference group (80 g/kg and 1.4:1 ratio).
Results: Dietary lipid and sex interacted in their effects on body weight (P = 0.015), total body length (P = 0.003), and total lipid mass (P = 0.029); thus, these analyses were stratified by sex. Female spawning success decreased as dietary total lipid and fatty acid ratio increased (P = 0.030 and P = 0.026, respectively). While total egg production was not associated with either dietary lipid component, females fed the 5:1 ratio produced higher proportions of viable embryos compared with the 1.4:1 ratio [median (95% CI): 0.915 (0.863, 0.956) vs 0.819 (0.716, 0.876); P < 0.001].
Conclusions: Further characterization of dietary lipid requirements will help define healthy balances of dietary lipid, while the sex-specific responses to dietary lipid identified in this study may partially explain sex disparities in the development of obesity and its comorbidities.

PMID: 32258992 [PubMed]

Alzheimer's disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?

Biochem Pharmacol. 2020 07;177:113945

Authors: Mullane K, Williams M

Abstract
Alzheimer's Disease (AD) therapeutics based on the amyloid hypothesis have repeatedly failed in clinical trials. Together with numerous reports that amyloid is present in brains from aged individuals without cognitive dysfunction, this suggests that the association of amyloid with AD is collateral rather than causal. However, the preeminence of the amyloid hypothesis has resulted in the 'systematic …thwart[ing of] alternative approaches' to AD/dementia driven by a 'cabal' of amyloid acolytes who have effectively controlled the ideas funded and published, which startups received venture investment and which programs were advanced in biopharmaceutical companies where they consulted. As a result, dementia research is estimated to be 15-30 years behind where it could be with conflicting data ignored in favor of the amyloid dogma and clinical trial failures being ascribed to faulty design or inadequacies in the compound selection process including flawed animal models. Major concerns regarding the precise diagnosis of AD/dementia and conflicting views on the validated status of fluid biomarker assays have resulted in trials that included patients with unknown amyloid pathologies. With the failure of the amyloid approach, emerging data on the role(s) of vascular, mitochondrial and synaptic network dysfunction, infection, diabetes, sleep, hearing loss, the gut microbiome and neuroinflammation/ innate immune function as dementia targets are driving research in new directions bolstered by recent findings on the genetic, omics and systems biology associated with AD/dementia. In moving forward, lessons learnt from the amyloid debacle should be used to enhance the objective identification of AD/dementia therapeutics as a multifactorial disease syndrome.

PMID: 32247851 [PubMed - indexed for MEDLINE]

Feasibility and safety of transradial access for pediatric neurointerventions.

J Neurointerv Surg. 2020 Sep;12(9):893-896

Authors: Srinivasan VM, Hadley CC, Prablek M, LoPresti M, Chen SH, Peterson EC, Sweid A, Jabbour P, Young C, Levitt M, Osbun JW, Burkhardt JK, Johnson J, Kan P

Abstract
BACKGROUND: Diagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients.
METHODS: A multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed.
RESULTS: Thirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal.
CONCLUSIONS: Transradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits.

PMID: 32241922 [PubMed - indexed for MEDLINE]

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Neurosurg Focus. 2020 Apr 01;48(4):E9

Authors: Young CC, Williams JR, Feroze AH, McGrath M, Ravanpay AC, Ellenbogen RG, Ojemann JG, Hauptman JS

Abstract
Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

PMID: 32234987 [PubMed - in process]

DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.

Epigenetics. 2020 Apr 01;:1-10

Authors: Jones GT, Marsman J, Bhat B, Phillips VL, Chatterjee A, Rodger EJ, Williams MJA, van Rij AM, McCormick SPA

Abstract
Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF <0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.

PMID: 32237968 [PubMed - as supplied by publisher]

WHO malaria nucleic acid amplification test external quality assessment scheme: results of distribution programmes one to three.

Malar J. 2020 Mar 30;19(1):129

Authors: Cunningham JA, Thomson RM, Murphy SC, de la Paz Ade M, Ding XC, Incardona S, Legrand E, Lucchi NW, Menard D, Nsobya SL, Saez AC, Chiodini PL, Shrivastava J

Abstract
BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria. In recent years, there has been surge in the use of various kinds of nucleic-acid amplification based tests (NAATs) for detection and identification of Plasmodium spp. to support clinical care in high-resource settings and clinical and epidemiological research worldwide. However, these tests are not without challenges, including lack (or limited use) of standards and lack of reproducibility, due in part to variation in protocols amongst laboratories. Therefore, there is a need for rigorous quality control, including a robust external quality assessment (EQA) scheme targeted towards malaria NAATs. To this effect, the WHO Global Malaria Programme worked with the UK National External Quality Assessment Scheme (UK NEQAS) Parasitology and with technical experts to launch a global NAAT EQA scheme in January 2017.
METHODS: Panels of NAAT EQA specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were tested and validated by six expert referee laboratories prior to distribution. Between 37 and 45 laboratories participated in each distribution and submitted results using the online submission portal of UK NEQAS. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers.
RESULTS: Analysis of the first three distributions revealed that the factors that most significantly affected performance were sample format (DBS vs LB), species and parasite density, while laboratory location and the reported methodology used (type of nucleic acid extraction, amplification, or DNA vs RNA target) did not significantly affect performance. Referee laboratories performed better than non-referee laboratories.
CONCLUSIONS: Globally, malaria NAAT assays now inform a range of clinical, epidemiological and research investigations. EQA schemes offer a way for laboratories to assess and improve their performance, which is critical to safeguarding the reliability of data and diagnoses especially in situations where various NAAT methodologies and protocols are in use.

PMID: 32228615 [PubMed - indexed for MEDLINE]

Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy.

Oncoimmunology. 2020;9(1):1730538

Authors: Georganaki M, Ramachandran M, Tuit S, Núñez NG, Karampatzakis A, Fotaki G, van Hooren L, Huang H, Lugano R, Ulas T, Kaunisto A, Holland EC, Ellmark P, Mangsbo SM, Schultze J, Essand M, Tugues S, Dimberg A

Abstract
CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.

PMID: 32231867 [PubMed]

Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.

J Empir Res Hum Res Ethics. 2019 02;14(1):49-60

Authors: Kraft SA, Duenas DM, Kublin JG, Shipman KJ, Murphy SC, Shah SK

Abstract
Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants' understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.

PMID: 30585505 [PubMed - indexed for MEDLINE]