UW Neurological Surgery Recent PubMed Publications

Alzheimer's disease (AD) therapeutics - 2: Beyond amyloid - Re-defining AD and its causality to discover effective therapeutics.

Biochem Pharmacol. 2018 12;158:376-401

Authors: Mullane K, Williams M

Abstract
Compounds targeted for the treatment of Alzheimer's Disease (AD) have consistently failed in clinical trials despite evidence for target engagement and pharmacodynamic activity. This questions the relevance of compounds acting at current AD drug targets - the majority of which reflect the seminal amyloid and, to a far lesser extent, tau hypotheses - and limitations in understanding AD causality as distinct from general dementia. The preeminence of amyloid and tau led to many alternative approaches to AD therapeutics being ignored or underfunded to the extent that their causal versus contributory role in AD remains unknown. These include: neuronal network dysfunction; cerebrovascular disease; chronic, local or systemic inflammation involving the innate immune system; infectious agents including herpes virus and prion proteins; neurotoxic protein accumulation associated with sleep deprivation, circadian rhythm and glymphatic/meningeal lymphatic system and blood-brain-barrier dysfunction; metabolic related diseases including diabetes, obesity hypertension and hypocholesterolemia; mitochondrial dysfunction and environmental factors. As AD has become increasingly recognized as a multifactorial syndrome, a single treatment paradigm is unlikely to work in all patients. However, the biomarkers required to diagnose patients and parse them into mechanism/disease-based sub-groups remain rudimentary and unvalidated as do non-amyloid, non-tau translational animal models. The social and economic impact of AD is also discussed in the context of new FDA regulatory draft guidance and a proposed biomarker-based Framework (re)-defining AD and its stages as part of the larger landscape of treating dementia via the 2013 G8 initiative to identify a disease-modifying therapy for dementia/AD by 2025.

PMID: 30273552 [PubMed - indexed for MEDLINE]

Alzheimer's disease (AD) therapeutics - 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality.

Biochem Pharmacol. 2018 12;158:359-375

Authors: Mullane K, Williams M

Abstract
Deposits of amyloid plaques and neurofibrillary tangles of aggregated tau in the brain represent key hallmarks of the neurodegenerative disorder, Alzheimer's Disease (AD) and form the basis of the major hypotheses of AD causality. To date, therapeutics that reduce brain amyloid in AD patients have demonstrated no effect in reversing the associated decline in cognition or function indicating that the amyloid hypothesis is either incorrect or that there is a point when the disease becomes independent of Aβ production or is refractory to any type of therapeutic intervention. The clinical failures of inhibitors of tau aggregation, neurotransmitter modulators and drugs repurposed from AD-associated disease indications tend to support this latter viewpoint. Current understanding of AD causality is thus incomplete, a situation that has been compounded by a debate on whether AD is a singularly distinct form of dementia and by the dogmatic promotion of hypotheses over actual clinical data. The latter has repeatedly led to compounds lacking efficacy in Phase II trials being advanced into Phase III where their lack of efficacy is routinely recapitulated. This Commentary, the first of two, discusses amyloid and tau as putative drug targets for AD in the context of the prevalence and economic and social impact of this insidious neurodegenerative disease.

PMID: 30273553 [PubMed - indexed for MEDLINE]

Outcome after myocardial infarction without obstructive coronary artery disease.

Heart. 2019 04;105(7):524-530

Authors: Williams MJA, Barr PR, Lee M, Poppe KK, Kerr AJ

Abstract
OBJECTIVE: The medium-term outcome and cause of death in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is not well characterised. The aim of this study was to compare mortality and rates of recurrent events in post myocardial infarction (MI) patients with obstructive coronary artery disease (CAD) and in patients with MINOCA compared with an age and sex-matched cohort without cardiovascular disease (CVD).
METHODS: We performed a national cohort study of consecutive patients undergoing coronary angiography for MI during 2 years between 2013 and 2015 from the All New Zealand Acute Coronary Syndrome-Quality Improvement (ANZACS QI) registry. MI patient registry data were linked anonymously to national hospitalisation and mortality records. Age and sex matched patients without known CVD formed the comparison group.
RESULTS: Of the 8305 patients with MI, 897 (10.8%) were classified as MINOCA. Compared with those without known CVD, the adjusted HRs for the primary outcome (all-cause death or recurrent non-fatal MI) were 7.81 (95% CI 6.64 to 9.19, p<0.0001) in those with obstructive CAD and 4.64 (95% CI 3.54 to 6.10, p<0.0001) in those with MINOCA. Kaplan-Meier all-cause mortality at 2 years was 7.9% for those with obstructive CAD, with nearly half being CVD deaths (3.6% CVD deaths and 4.5% non-CVD deaths, respectively). In contrast, MINOCA all-cause mortality was 4.9% with non-CVD death (4.5%) predominating.
CONCLUSIONS: MINOCA is common and has an adverse outcome rate approximately half than that of those with obstructive CAD. The predominant contributor to mortality is non-CVD death. The rate of events in MINOCA is significantly greater than the population without CVD.

PMID: 30269079 [PubMed - indexed for MEDLINE]

Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma.

Fam Cancer. 2019 04;18(2):241-251

Authors: Walker EJ, Carnevale J, Pedley C, Blanco A, Chan S, Collisson EA, Tempero MA, Ko AH

Abstract
Hereditary predisposition is estimated to account for 10% of all pancreatic cancer cases. However, referral patterns and clinical workflow for germline testing in this disease differ significantly by institution, and many at-risk patients may not undergo appropriate counseling and testing. We undertook an analysis of patients diagnosed with pancreatic cancer (PDAC) who were referred to the Clinical Genetics program of a high-volume academic center over a 3-year period to assess referral frequency, evaluate the yield of germline testing in this selected patient cohort, and elucidate the reasons individuals did not undergo recommended germline testing. Medical records of patients with PDAC referred for genetic counseling between January 2015 and October 2017 were reviewed for demographic, medical/family history, and disease-specific data. If testing did not occur, reasons were documented. Genetic test results were categorized as negative, variants of unknown significance, or established pathogenic mutations. Descriptive statistics included means with standard deviations; associations were analyzed with t test and Fisher's exact test. 32% (137 of 432) of PDAC patients were referred for genetic counseling, but only 64% attended their appointment and 60% ultimately underwent germline testing. Common reasons for attrition included worsening disease severity, lack of patient follow-up, insurance concerns, and logistic/travel challenges. Pathogenic germline mutations were detected in 20% (16 of 82) of patients tested, distributed across races/ethnicities, and significantly associated with younger age and positive family history of breast cancer. PDAC patients frequently do not undergo genetic counseling/germline testing despite appropriate referrals, highlighting a need to develop streamlined processes to engage more patients in testing, especially those with high-risk features.

PMID: 30267352 [PubMed - indexed for MEDLINE]

A clinical decision rule to predict intracranial hypertension in severe traumatic brain injury.

J Neurosurg. 2018 09 28;131(2):612-619

Authors: Alali AS, Temkin N, Barber J, Pridgeon J, Chaddock K, Dikmen S, Hendrickson P, Videtta W, Lujan S, Petroni G, Guadagnoli N, Urbina Z, Chesnut RM

Abstract
OBJECTIVE: While existing guidelines support the treatment of intracranial hypertension in severe traumatic brain injury (TBI), it is unclear when to suspect and initiate treatment for high intracranial pressure (ICP). The objective of this study was to derive a clinical decision rule that accurately predicts intracranial hypertension.
METHODS: Using Delphi methods, the authors identified a set of potential predictors of intracranial hypertension and a clinical decision rule a priori by consensus among a group of 43 neurosurgeons and intensivists who have extensive experience managing severe TBI without ICP monitoring. To validate these predictors, the authors used data from a Latin American trial (n = 150; BEST TRIP). To report on the performance of the rule, they calculated sensitivity, specificity, and positive and negative predictive values with 95% confidence intervals. In a secondary analysis, the rule was validated using data from a North American trial (n = 131; COBRIT).
RESULTS: The final predictors and the clinical decision rule were approved by 97% of participants in the consensus working group. The predictors are divided into major and minor criteria. High ICP would be considered suspected in the presence of 1 major or ≥ 2 minor criteria. Major criteria are: compressed cisterns (CT classification of Marshall diffuse injury [DI] III), midline shift > 5 mm (Marshall DI IV), or nonevacuated mass lesion. Minor criteria are: Glasgow Coma Scale (GCS) motor score ≤ 4, pupillary asymmetry, abnormal pupillary reactivity, or Marshall DI II. The area under the curve for the logistic regression model that contains all the predictors was 0.86. When high ICP was defined as > 22 mm Hg, the decision rule performed with a sensitivity of 93.9% (95% CI 85.0%-98.3%), a specificity of 42.3% (95% CI 31.7%-53.6%), a positive predictive value of 55.5% (95% CI 50.7%-60.2%), and a negative predictive value of 90% (95% CI 77.1%-96.0%). The sensitivity of the clinical decision rule improved with higher ICP cutoffs up to a sensitivity of 100% when intracranial hypertension was defined as ICP > 30 mm Hg. Similar results were found in the North American cohort.
CONCLUSIONS: A simple clinical decision rule based on a combination of clinical and imaging findings was found to be highly sensitive in distinguishing patients with severe TBI who would suffer intracranial hypertension. It could be used to identify patients who require ICP monitoring in high-resource settings or start ICP-lowering treatment in environments where resource limitations preclude invasive monitoring.Clinical trial registration no.: NCT02059941 (clinicaltrials.gov).

PMID: 30265194 [PubMed - indexed for MEDLINE]

Internal decompression of the acutely contused spinal cord: Differential effects of irrigation only versus biodegradable scaffold implantation.

Biomaterials. 2018 12;185:284-300

Authors: Guest JD, Moore SW, Aimetti AA, Kutikov AB, Santamaria AJ, Hofstetter CP, Ropper AE, Theodore N, Ulich TR, Layer RT

Abstract
Severe spinal cord injury leads to hemorrhage, edema and elevated tissue pressures that propagate ischemia. Liquefactive necrosis of damaged tissue eventually results in chronic cavities due to a wound healing process lacking adhesive contractile cells. Biomaterials can potently influence wound healing responses. Internal decompression (ID) refers to pial opening, allowing spontaneous extrusion and irrigation of fluid necrotic debris relieving pressure and resulting in a space for biomaterial scaffold insertion. After thoracic contusions, rats were randomized to: contusion only, contusion + ID and contusion + ID + PLGA-PLL scaffold implantation, to test for neuroprotection and endogenous repair over 3 months. ID alone reduced inflammatory activity, cavity volume, and increased tissue sparing. Scaffold biodegradation produced delayed ingrowth of inflammatory and other cells resulting in endogenously derived laminin-rich tissue, marked reduction in cavitation and presence of tissue remodeling macrophages. Extensive recruitment of Schwann cells into adjacent spared white matter occurred, greatest in scaffold-implanted animals. Despite tissue preservation with myelin repair, no groups differed significantly in open field locomotion. However, across all rats, spared epicenter tissue and locomotor outcomes were correlated. Scaffold-implanted animals showed no obvious toxicity. To study the clinical feasibility, timing and indications for scaffold implantation, Göttingen minipigs underwent ID and were implanted with scaffolds 4, 6, and 24 h after T10 contusion. High intra-spinal tissue pressures fell to pre-injury levels after ID and scaffold implantation. Extrusion of necrotic debris left sufficient space for a sized scaffold. These results provided the preclinical rationale for a current clinical study of biomaterial scaffold implantation into the human injured spinal cord.

PMID: 30265898 [PubMed - indexed for MEDLINE]

cIMPACT-NOW update 3: recommended diagnostic criteria for "Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV".

Acta Neuropathol. 2018 11;136(5):805-810

Authors: Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, Kleinschmidt-DeMasters BK, Perry A, Reifenberger G, Stupp R, von Deimling A, Weller M

Abstract

PMID: 30259105 [PubMed - indexed for MEDLINE]

Sparse recurrent excitatory connectivity in the microcircuit of the adult mouse and human cortex.

Elife. 2018 Sep 26;7:

Authors: Seeman SC, Campagnola L, Davoudian PA, Hoggarth A, Hage TA, Bosma-Moody A, Baker CA, Lee JH, Mihalas S, Teeter C, Ko AL, Ojemann JG, Gwinn RP, Silbergeld DL, Cobbs C, Phillips J, Lein E, Murphy G, Koch C, Zeng H, Jarsky T

Abstract
Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, we have begun a pipeline project using multipatch electrophysiology, supplemented with two-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse primary visual cortex (V1) and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here, we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell classes and layers we sampled, and that most mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons, however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.

PMID: 30256194 [PubMed - in process]

Semi-autonomous image-guided brain tumour resection using an integrated robotic system: A bench-top study.

Int J Med Robot. 2018 Feb;14(1):

Authors: Hu D, Gong Y, Seibel EJ, Sekhar LN, Hannaford B

Abstract
BACKGROUND: Complete brain tumour resection is an extremely critical factor for patients' survival rate and long-term quality of life. This paper introduces a prototype medical robotic system that aims to automatically detect and clean up brain tumour residues after the removal of tumour bulk through conventional surgery.
METHODS: We focus on the development of an integrated surgical robotic system for image-guided robotic brain surgery. The Behavior Tree framework is explored to coordinate cross-platform medical subtasks.
RESULTS: The integrated system was tested on a simulated laboratory platform. Results and performance indicate the feasibility of supervised semi-automation for residual brain tumour ablation in a simulated surgical cavity with sub-millimetre accuracy. The modularity in the control architecture allows straightforward integration of further medical devices.
CONCLUSIONS: This work presents a semi-automated laboratory setup, simulating an intraoperative robotic neurosurgical procedure with real-time endoscopic image guidance and provides a foundation for the future transition from engineering approaches to clinical application.

PMID: 29105281 [PubMed - indexed for MEDLINE]

Evaluating a Targeted Bedside Measure of Cerebral Perfusion in a Nonhuman Primate Model of Neonatal Hypoxic-Ischemic Encephalopathy.

J Ultrasound Med. 2018 Apr;37(4):913-920

Authors: Peeples ES, Ezeokeke CK, Juul SE, Mourad PD

Abstract
OBJECTIVES: To compare ultrasound-derived resistive indices (RIs) obtained at the level of the thalamus via fast Doppler ultrasound with traditional anterior cerebral artery measures in a model of neonatal hypoxic-ischemic encephalopathy and to correlate each with clinical outcomes.
METHODS: Nine nonhuman primate neonates underwent no umbilical cord occlusion (n = 3), umbilical cord occlusion without hypothermia (n = 3), or umbilical cord occlusion with hypothermia (n = 3). The RI was measured in the anterior cerebral artery and thalamus on days 0, 1, and 4 of life. Magnetic resonance imaging with spectroscopy was performed on day 4.
RESULTS: Mean thalamus and anterior cerebral artery RI values in the first 36 hours of life were statistically different in neonates who died (+0.13; P = .019) or developed cerebral palsy (-0.08; P = .003). Thalamic RI values showed stronger associations with serum and spectroscopic lactate values than those in the anterior cerebral artery. The umbilical cord occlusion-with-hypothermia group showed a significant increase in the RI in the thalamus but not the anterior cerebral artery.
CONCLUSIONS: Resistive index measurements in the thalamus may eventually supplement other bedside measures for predicting outcomes in the HIE population, but further studies need to differentiate the effect of hypothermia from illness severity on thalamic perfusion.

PMID: 28960438 [PubMed - indexed for MEDLINE]

Would the control of invasive alien plants reduce malaria transmission? A review.

Parasit Vectors. 2018 02 01;11(1):76

Authors: Stone CM, Witt ABR, Walsh GC, Foster WA, Murphy ST

Abstract
Vector control has been the most effective preventive measure against malaria and other vector-borne diseases. However, due to concerns such as insecticide resistance and budget shortfalls, an integrated control approach will be required to ensure sustainable, long-term effectiveness. An integrated management strategy should entail some aspects of environmental management, relying on coordination between various scientific disciplines. Here, we review one such environmental control tactic: invasive alien plant management. This covers salient plant-mosquito interactions for both terrestrial and aquatic invasive plants and how these affect a vector's ability to transmit malaria. Invasive plants tend to have longer flowering durations, more vigorous growth, and their spread can result in an increase in biomass, particularly in areas where previously little vegetation existed. Some invasive alien plants provide shelter or resting sites for adult mosquitoes and are also attractive nectar-producing hosts, enhancing their vectorial capacity. We conclude that these plants may increase malaria transmission rates in certain environments, though many questions still need to be answered, to determine how often this conclusion holds. However, in the case of aquatic invasive plants, available evidence suggests that the management of these plants would contribute to malaria control. We also examine and review the opportunities for large-scale invasive alien plant management, including options for biological control. Finally, we highlight the research priorities that must be addressed in order to ensure that integrated vector and invasive alien plant management operate in a synergistic fashion.

PMID: 29391041 [PubMed - indexed for MEDLINE]

Functional independence after acquired brain injury: Prospective effects of health self-efficacy and cognitive impairment.

Rehabil Psychol. 2018 Nov;63(4):595-603

Authors: Parker HA, Rapport LJ, Williams MW, Hanks RA, Lumley MA, Bogg T

Abstract
OBJECTIVE: To examine how health self-efficacy and cognitive impairment severity relate to functional independence after acquired brain injury (ABI).
DESIGN: Observational.
SETTING: Outpatient rehabilitation hospital.
PARTICIPANTS: Seventy-five adults with predominately stroke or traumatic brain injury who were beginning a course of occupational therapy.
MAIN MEASURES: Health self-efficacy was assessed with the Self-Rated Abilities for Health Practices. Cognitive functioning was assessed via a composite z score of neuropsychological tests. Trait affectivity was assessed with the Positive and Negative Affect Schedule. Functional independence was assessed with the Barthel Index and Lawton Instrumental Activities of Daily Living Scale.
RESULTS: Health self-efficacy correlated moderately with functional independence. A moderation threshold effect was detected that revealed for whom health self-efficacy predicted functional independence. Among participants with normal to mildly impaired cognition (>-2 z cognitive composite), health self-efficacy correlated positively with functional independence, which held after accounting for trait affectivity. In contrast, health self-efficacy was not correlated with functional independence among participants with greater impairment (<-2 z cognitive composite).
CONCLUSIONS: Health self-efficacy predicts functional independence and may serve as a protective factor after ABI among individuals with relatively intact cognition. However, health self-efficacy does not predict functional independence among individuals with moderate or severe cognitive impairment, possibly due to limited self-awareness. This study extends the literature linking health self-efficacy with rehabilitation outcomes and reinforces the need for promoting self-management in ABI. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

PMID: 30247052 [PubMed - indexed for MEDLINE]

Criminal justice measures for economic data harmonization in substance use disorder research.

Health Justice. 2018 Sep 21;6(1):17

Authors: McCollister KE, Yang X, Murphy SM, Leff JA, Kronmal RA, Crane HM, Chandler RK, Taxman FS, Feaster DJ, Metsch LR, Cunningham WE, Altice FL, Schackman BR

Abstract
BACKGROUND: The consequences of substance use disorders (SUDs) are varied and broad, affecting many sectors of society and the economy. Economic evaluation translates these consequences into dollars to examine the net economic impact of interventions for SUD, and associated conditions such as HCV and HIV. The nexus between substance use and crime makes criminal justice outcomes particularly significant for estimating the economic impact of SUD interventions, and important for data harmonization.
METHODS: We compared baseline data collected in six NIDA-funded Seek, Test, Treat and Retain (STTR) intervention studies that enrolled HIV-infected/at-risk individuals with SUDs (total n = 3415). Criminal justice measures included contacts with the criminal justice system (e.g., arrests) and criminal offenses. The objective was to develop a list of recommended measures and methods supporting economic data harmonization opportunities in HIV and SUD research, with an initial focus on crime-related outcomes.
RESULTS: Criminal justice contacts and criminal offenses were highly variable across studies. When measures grouped by offense classifications were compared, consistencies across studies emerged. Most individuals report being arrested for property or public order crimes (> 50%); the most commonly reported offenses were prostitution/pimping, larceny/shoplifting, robbery, and household burglary.
CONCLUSIONS: We identified four measures that are feasible and appropriate for estimating the economic consequences of SUDs/HIV/HCV: number of arrests, number of convictions, days of incarceration, and times committing criminal offenses, by type of offense. To account for extreme variation, grouping crimes by offense classification or calculating monthly averages per event allows for more meaningful comparisons across studies.

PMID: 30242561 [PubMed]

Vessel wall MRI characteristics of endovascularly treated aneurysms: association with angiographic vasospasm.

J Neurosurg. 2018 09 21;131(3):859-867

Authors: Mossa-Basha M, Huynh TJ, Hippe DS, Fata P, Morton RP, Levitt MR

Abstract
OBJECTIVE: The aim of this paper was to evaluate the association between intracranial vessel wall MRI enhancement characteristics and the development of angiographic vasospasm in endovascularly treated aneurysm patients.
METHODS: Consecutive cases of both ruptured and unruptured intracranial aneurysms that were treated endovascularly, followed by intracranial vessel wall MRI in the immediate postoperative period, were included. Two raters blinded to clinical data and follow-up imaging independently evaluated for the presence, pattern, and intensity of wall enhancement. Development of angiographic vasospasm was independently evaluated. Delayed cerebral ischemia; cerebral infarct; procedural details; and presence and grade of subarachnoid, parenchymal, and intraventricular hemorrhage were evaluated. Statistical associations were determined on a per-vessel segment and per-patient basis.
RESULTS: Twenty-nine patients with 30 treated aneurysms (8 unruptured and 22 ruptured) were included in this study. Interobserver agreement was substantial for the presence of enhancement (κ = 0.67) and nearly perfect for distribution (κ = 0.87) and intensity (κ = 0.84) of wall enhancement. Patients with ruptured aneurysms had a significantly greater number of enhancing segments than those with unruptured aneurysms (29.9% vs 7.2%; OR 5.5, 95% CI 2.2-13.7). For ruptured cases, wall enhancement was significantly associated with subsequent angiographic vasospasm while controlling for grade of hemorrhage (adjusted OR 3.9, 95% CI 1.7-9.4). Vessel segments affected by balloon, stent, or flow-diverter use demonstrated greater enhancement than those not affected (OR 22.7, 95% CI 5.3-97.2 for ruptured; and OR 12.9, 95% CI 3.3-49.8 for unruptured).
CONCLUSIONS: Vessel wall enhancement after endovascular treatment of ruptured aneurysms is associated with subsequent angiographic vasospasm.

PMID: 30239313 [PubMed - indexed for MEDLINE]

Heterozygosity of Chaperone Grp78 Reduces Intestinal Stem Cell Regeneration Potential and Protects against Adenoma Formation.

Cancer Res. 2018 11 01;78(21):6098-6106

Authors: van Lidth de Jeude JF, Spaan CN, Meijer BJ, Smit WL, Soeratram TTD, Wielenga MCB, Westendorp BF, Lee AS, Meisner S, Vermeulen JLM, Wildenberg ME, van den Brink GR, Muncan V, Heijmans J

Abstract
Deletion of endoplasmic reticulum resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here, we employ a model of epithelial-specific, heterozygous Grp78 deletion by use of VillinCreERT2-Rosa26ZsGreen/LacZ-Grp78+/fl mice and organoids. We examine models of irradiation and tumorigenesis, both in vitro and in vivo Although we observed no phenotypic changes in Grp78 heterozygous mice, Grp78 heterozygous organoid growth was markedly reduced. Irradiation of Grp78 heterozygous mice resulted in less frequent regeneration of crypts compared with nonrecombined (wild-type) mice, exposing reduced capacity for self-renewal upon genotoxic insult. We crossed mice to Apc-mutant animals for adenoma studies and found that adenomagenesis in Apc heterozygous-Grp78 heterozygous mice was reduced compared with Apc heterozygous controls (1.43 vs. 3.33; P < 0.01). In conclusion, epithelium-specific Grp78 heterozygosity compromises epithelial fitness under conditions requiring expansive growth such as adenomagenesis or regeneration after γ-irradiation. These results suggest that Grp78 may be a therapeutic target in prevention of intestinal neoplasms without affecting normal tissue.Significance: Heterozygous disruption of chaperone protein Grp78 reduces tissue regeneration and expansive growth and protects from tumor formation without affecting intestinal homeostasis. Cancer Res; 78(21); 6098-106. ©2018 AACR.

PMID: 30232220 [PubMed - indexed for MEDLINE]

Economic evaluation of telephone-based concussion management for combat-related mild traumatic brain injury.

J Telemed Telecare. 2018 May;24(4):282-289

Authors: Richardson JS, Guzauskas GF, Fann JR, Temkin NR, Bush NE, Bell KR, Gahm GA, Smolenski DJ, Brockway JA, Hansen RN

Abstract
Introduction Mild traumatic brain injury (mTBI) is an unfortunately common repercussion of military service in a combat zone. The CONTACT study tested an individualized telephone support intervention employing problem solving therapy (PST) for mTBI in soldiers recently returned from deployment. We sought to determine the cost effectiveness of this intervention from a military healthcare system perspective. Methods We conducted an intent-to-treat post-hoc analysis by building a decision analytic model that evaluated the choice between using PST or education only (EO). The model included cost-minimization and cost-effectiveness analyses. The incremental cost-effectiveness ratios (ICERs) were calculated as the differences in costs of PST versus EO relative to the differences in the outcomes of participants. Results The PST intervention resulted in an annual per-enrolee cost of $1027 (95% CI: $836 to $1248), while EO costs were $32 (95% CI: $25 to $39), resulting in a net incremental cost of $996 per enrolee (95% CI: $806 to $1,217). The ICERs were $68,658/QALY based on EQ-5D (95% CI: -$463,535 to $596,661) and $49,284/QALY based on SF-6D (95% CI: $26,971 to $159,309). Estimates of treatment costs in a real-world setting were accompanied by substantially lower ICERs that are within accepted thresholds for willingness-to-pay. Discussion Although the intervention had short-term benefits sufficient to yield acceptable ICERs, there was no long-term effect of PST over EO observed in the study. Consequently, we suggest that future studies examine the use of low-cost approaches, such as booster relapse-prevention calls, that may lead to a sustained treatment benefit for this population.

PMID: 28372513 [PubMed - indexed for MEDLINE]

Intra- and Peri-operative Complications Associated with Endoscopic Spine Surgery: A multi-institutional study.

World Neurosurg. 2018 Sep 10;:

Authors: Sen RD, White-Dzuro G, Ruzevick J, Kim CW, Witt JP, Telfeian AE, Wang MY, Hofstetter CP

Abstract
OBJECT: The purpose of this study is to report on intra- and peri-operative complications associated with working channel endoscopic spine surgery.
METHODS: This study is a retrospective chart review of a multi-institutional patient cohort operated on by surgeons within the Endoscopic Spine Study Group (ESSG) between May, 2010 and June, 2017.
RESULTS: Our study cohort consisted of a total of 553 consecutive cases with an average age of 57 years. The most common procedure was an endoscopic discectomy (n = 377, 68%) followed by foraminotomy (n = 156, 28.2%), laminectomy (n = 55, 9.9%), and medial facetectomy (n = 29, 5.2%). Overall, the rate of intra- and perioperative complications was 2.7%. There were 3 durotomies (0.54%), 2 epidural hematomas (0.36%), 2 patients developed a complex pain disorder (0.36%), 4 recurrent disc herniations within 3 months (1.1%), 4 systemic complications (1.1%) and no wound infections. No risk factors were identified with regards to age, gender, approach or number of segments.
CONCLUSIONS: Endoscopic spine surgery is associated with favorable rates of intra- and peri-operative complications compared to literature reports of comparable MIS and open surgeries. Our report proposes safe and effective strategies for management of these complications.

PMID: 30213674 [PubMed - as supplied by publisher]

Methimazole-Induced Pauci-Immune Glomerulonephritis and Anti-Phospholipid Syndrome: An Important Association to Be Aware of.

J Clin Med Res. 2018 Oct;10(10):786-790

Authors: Qaisar H, Hossain MA, Akula M, Cheng J, Patel M, Min Z, Kuzyshyn H, Levitt M, Coley SM, Asif A

Abstract
While methimazole (MMI) is the first line treatment for hyperthyroidism, this medication is not devoid of adverse effects. In this article, we present a 70-year-old male who admitted the hospital with right lower extremity pain and rash. The patient was recently treated with MMI for hyperthyroidism. Imaging studies revealed bilateral renal and splenic infarcts along with thrombosis of popliteal artery. Laboratory data revealed hematuria and proteinuria with positive (MPO), anti-proteinase-3 (PR3) and anti-cardiolipin IgG antibodies. Renal biopsy revealed pauci-immune glomerulonephritis and features with anti-phospholipid antibody syndrome (APS). MMI was discontinued and the patient was treated successfully with steroid therapy and anti-coagulation with resolution of proteinuria, hematuria and normalization of laboratory parameters. While MMI-induced pauci-immune glomerulonephritis has been previously reported, its association with APS has never been described before. Our case demonstrates that this rare diagnosis can be treated by early withdrawal of MMI and initiation of steroids along with anticoagulation.

PMID: 30214651 [PubMed]

Dabigatran-Induced Acute Interstitial Nephritis: An Important Complication of Newer Oral Anticoagulation Agents.

J Clin Med Res. 2018 Oct;10(10):791-794

Authors: Patel S, Hossain MA, Ajam F, Patel M, Nakrani M, Patel J, Alhillan A, Hammoda M, Alrefaee A, Levitt M, Asif A

Abstract
Acute kidney injury (AKI) due to an acute interstitial nephritis (AIN) is common and can lead to increased morbidity and mortality. Medications such as antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPI) and rifampin are common offending agents. Anticoagulant-associated AIN is more frequently reported with the use of warfarin; however, only few case reports have reported an association with the use of novel oral anticoagulants (NOACs). Herein, we report the case of a 59-year-old male who developed AKI after initiating dabigatran for the treatment of atrial fibrillation. Laboratory data demonstrated elevated blood urea nitrogen (BUN) of 115 mg/dL (baseline = 35 mg/dL) and serum creatinine (Cr) of 5.06 mg/dL (baseline = 1.3 mg/dL). Urinalysis revealed eosinophiluria. Renal biopsy disclosed diffuse tubulointerstitial nephritis and eosinophils and confirmed the diagnosis of AIN. At 1 week, renal function improved (BUN/Cr = 53/2.73 mg/dL) with steroid therapy and discontinuation of dabigatran. With an increasing use of NOACs, it is important to monitor renal function to diagnose AIN in a timely fashion. Early diagnosis and prompt treatment can mitigate serious renal damage induced by dabigatran.

PMID: 30214652 [PubMed]

Development of best practices to minimize wound complications after complex tethered spinal cord surgery: a modified Delphi study.

J Neurosurg Pediatr. 2018 Dec 01;22(6):701-709

Authors: Alexiades NG, Ahn ES, Blount JP, Brockmeyer DL, Browd SR, Grant GA, Heuer GG, Hankinson TC, Iskandar BJ, Jea A, Krieger MD, Leonard JR, Limbrick DD, Maher CO, Proctor MR, Sandberg DI, Wellons JC, Shao B, Feldstein NA, Anderson RCE

Abstract
OBJECTIVEComplications after complex tethered spinal cord (cTSC) surgery include infections and cerebrospinal fluid (CSF) leaks. With little empirical evidence to guide management, there is variability in the interventions undertaken to limit complications. Expert-based best practices may improve the care of patients undergoing cTSC surgery. Here, authors conducted a study to identify consensus-driven best practices.METHODSThe Delphi method was employed to identify consensual best practices. A literature review regarding cTSC surgery together with a survey of current practices was distributed to 17 board-certified pediatric neurosurgeons. Thirty statements were then formulated and distributed to the group. Results of the second survey were discussed during an in-person meeting leading to further consensus, which was defined as ≥ 80% agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree).RESULTSSeventeen consensus-driven best practices were identified, with all participants willing to incorporate them into their practice. There were four preoperative interventions: (1, 2) asymptomatic AND symptomatic patients should be referred to urology preoperatively, (3, 4) routine preoperative urine cultures are not necessary for asymptomatic AND symptomatic patients. There were nine intraoperative interventions: (5) patients should receive perioperative cefazolin or an equivalent alternative in the event of allergy, (6) chlorhexidine-based skin preparation is the preferred regimen, (7) saline irrigation should be used intermittently throughout the case, (8) antibiotic-containing irrigation should be used following dural closure, (9) a nonlocking running suture technique should be used for dural closure, (10) dural graft overlay should be used when unable to obtain primary dural closure, (11) an expansile dural graft should be incorporated in cases of lipomyelomeningocele in which primary dural closure does not permit free flow of CSF, (12) paraxial muscles should be closed as a layer separate from the fascia, (13) routine placement of postoperative drains is not necessary. There were three postoperative interventions: (14) postoperative antibiotics are an option and, if given, should be discontinued within 24 hours; (15) patients should remain flat for at least 24 hours postoperatively; (16) routine use of abdominal binders or other compressive devices postoperatively is not necessary. One intervention was prioritized for additional study: (17) further study of additional gram-negative perioperative coverage is needed.CONCLUSIONSA modified Delphi technique was used to develop consensus-driven best practices for decreasing wound complications after cTSC surgery. Further study is required to determine if implementation of these practices will lead to reduced complications. Discussion through the course of this study resulted in the initiation of a multicenter study of gram-negative surgical site infections in cTSC surgery.

PMID: 30215584 [PubMed - indexed for MEDLINE]