UW Neurological Surgery Recent PubMed Publications

CG4928 Is Vital for Renal Function in Fruit Flies and Membrane Potential in Cells: A First In-Depth Characterization of the Putative Solute Carrier UNC93A.

Front Cell Dev Biol. 2020;8:580291

Authors: Ceder MM, Aggarwal T, Hosseini K, Maturi V, Patil S, Perland E, Williams MJ, Fredriksson R

Abstract
The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK1 channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

PMID: 33163493 [PubMed]

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Biomed Res Int. 2020;2020:2608318

Authors: Levitt DG, Levitt JE, Levitt MD

Abstract
Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

PMID: 33150168 [PubMed - in process]

Health economic design for cost, cost-effectiveness and simulation analyses in the HEALing Communities Study.

Drug Alcohol Depend. 2020 Oct 03;217:108336

Authors: Aldridge AP, Barbosa C, Barocas JA, Bush JL, Chhatwal J, Harlow KJ, Hyder A, Linas BP, McCollister KE, Morgan JR, Murphy SM, Savitzky C, Schackman BR, Seiber EE, E Starbird L, Villani J, Zarkin GA

Abstract
BACKGROUND: The HEALing Communities Study (HCS) is designed to implement and evaluate the Communities That HEAL (CTH) intervention, a conceptually driven framework to assist communities in selecting and adopting evidence-based practices to reduce opioid overdose deaths. The goal of the HCS is to produce generalizable information for policy makers and community stakeholders seeking to implement CTH or a similar community intervention. To support this objective, one aim of the HCS is a health economics study (HES), the results of which will inform decisions around fiscal feasibility and sustainability relevant to other community settings.
METHODS: The HES is integrated into the HCS design: an unblinded, multisite, parallel arm, cluster randomized, wait list-controlled trial of the CTH intervention implemented in 67 communities in four U.S. states: Kentucky, Massachusetts, New York, and Ohio. The objectives of the HES are to estimate the economic costs to communities of implementing and sustaining CTH; estimate broader societal costs associated with CTH; estimate the cost-effectiveness of CTH for overdose deaths avoided; and use simulation modeling to evaluate the short- and long-term health and economic impact of CTH, including future overdose deaths avoided and quality-adjusted life years saved, and to develop a simulation policy tool for communities that seek to implement CTH or a similar community intervention.
DISCUSSION: The HCS offers an unprecedented opportunity to conduct health economics research on solutions to the opioid crisis and to increase understanding of the impact and value of complex, community-level interventions.

PMID: 33152672 [PubMed - as supplied by publisher]

Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome.

Neurobiol Dis. 2020 Oct 31;:105154

Authors: Sahai N, Bard AM, Devinsky O, Kalume F

Abstract
OBJECTIVE: To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS).
METHODS: We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise.
RESULTS: Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods.
SIGNIFICANCE: We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.

PMID: 33144172 [PubMed - as supplied by publisher]

A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge.

mBio. 2020 Nov 03;11(6):

Authors: Morrison SG, Giebel AM, Toh E, Banerjee A, Nelson DE, Morrison RP

Abstract
Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease.IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.

PMID: 33144378 [PubMed - in process]

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon.

Neurosurg Focus. 2020 Nov;49(5):E23

Authors: Bass DI, Lee A, Browd SR, Ellenbogen RG, Hauptman JS

Abstract
The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.

PMID: 33130608 [PubMed - in process]

The effect of durotomy versus myelotomy on tissue sparing and functional outcome after spinal cord injury.

J Neurotrauma. 2020 Oct 29;:

Authors: Khaing ZZ, Cates LN, Dewees DM, Hyde JE, Gaing A, Birjandian Z, Hofstetter CP

Abstract
Various surgical strategies have been developed to alleviate elevated intraspinal pressure (ISP) following acute traumatic spinal cord injury (tSCI). Surgical decompression of either the dural (durotomy) or the dural and pial (myelotomy) lining of the spinal cord has been proposed. However, a direct comparison of these two strategies is lacking. Here, we compare the histological and functional effects of durotomy alone and durotomy + myelotomy in a rodent model of acute thoracic tSCI. Our results indicate that tSCI causes local tissue edema and significantly elevates intraspinal pressure (ISP, 7.4 ± 0.3 mmHg) compared to physiological ISP (1.7 ± 0.4 mmHg; P < 0.001). Both durotomy alone and durotomy + myelotomy effectively mitigate elevated local ISP (P < 0.001). Histological examination at 10 weeks after tSCI revealed that durotomy + myelotomy promoted spinal tissue sparing by 13.7% compared to durotomy alone and by 25.9% compared to tSCI-only (P < 0.0001). Both types of decompression surgeries elicited a significant beneficial impact onto grey matter sparing (P < 0.01). Impressively, durotomy + myelotomy surgery increased preservation of motoneurons by 174.3% compared to tSCI-only (P < 0.05). Durotomy + myelotomy surgery also significantly promoted recovery of hindlimb locomotor function in an open-field test (P < 0.001). Interestingly, only durotomy alone resulted in favorable recovery of bladder and Ladder Walk performance. Combined, our data suggest that durotomy + myelotomy following acute tSCI facilitates tissue sparing and recovery of locomotor function. In the future, biomarkers identifying spinal cord injuries that can benefit from either durotomy alone or durotomy + myelotomy need to be developed.

PMID: 33121382 [PubMed - as supplied by publisher]

Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma.

J Immunother Cancer. 2020 Oct;8(2):

Authors: Gardell JL, Matsumoto LR, Chinn H, DeGolier KR, Kreuser SA, Prieskorn B, Balcaitis S, Davis A, Ellenbogen RG, Crane CA

Abstract
BACKGROUND: Targeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects.
METHODS: In this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo.
RESULTS: Transduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model.
CONCLUSIONS: The ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity.

PMID: 33122397 [PubMed - in process]

Expansile duraplasty and obex exploration compared with bone-only decompression for Chiari malformation type I in children: retrospective review of outcomes and complications.

J Neurosurg Pediatr. 2020 Oct 30;:1-8

Authors: Ene CI, Wang AC, Collins KL, Bonow RH, McGrath LB, Durfy SJ, Barber JK, Ellenbogen RG

Abstract
OBJECTIVE: While a select population of pediatric patients with Chiari malformation type I (CM-I) remain asymptomatic, some patients present with tussive headaches, neurological deficits, progressive scoliosis, and other debilitating symptoms that necessitate surgical intervention. Surgery entails a variety of strategies to restore normal CSF flow, including increasing the posterior fossa volume via bone decompression only, or bone decompression with duraplasty, with or without obex exploration. The indications for duraplasty and obex exploration following bone decompression remain controversial. The objective of this study was to describe an institutional series of pediatric patients undergoing surgery for CM-I, performed by a single neurosurgeon. For patients presenting with a syrinx, the authors compared outcomes following bone-only decompression with duraplasty only and with duraplasty including obex exploration. Clinical outcomes evaluated included resolution of syrinx, scoliosis, presenting symptoms, and surgical complications.
METHODS: A retrospective review was conducted of the medical records of 276 consecutive pediatric patients with CM-I operated on at a single institution between 2001 and 2015 by the senior author. Imaging findings of tonsillar descent, associated syrinx (syringomyelia or syringobulbia), basilar invagination, and clinical assessment of CM-I-attributable symptoms and scoliosis were recorded. In patients presenting with a syrinx, clinical outcomes, including syrinx resolution, symptom resolution, and impact on scoliosis progression, were compared for three surgical groups: bone-only/posterior fossa decompression (PFD), PFD with duraplasty (PFDwD), and PFD with duraplasty and obex exploration (PFDwDO).
RESULTS: PFD was performed in 25% of patients (69/276), PFDwD in 18% of patients (50/276), and PFDwDO in 57% of patients (157/276). The mean follow-up was 35 ± 35 months. Nearly half of the patients (132/276, 48%) had a syrinx. In patients presenting with a syrinx, PFDwDO was associated with a significantly higher likelihood of syrinx resolution relative to PFD only (HR 2.65, p = 0.028) and a significant difference in time to symptom resolution (HR 2.68, p = 0.033). Scoliosis outcomes did not differ among treatment groups (p = 0.275). Complications were not significantly higher when any duraplasty (PFDwD or PFDwDO) was performed following bone decompression (p > 0.99).
CONCLUSIONS: In this series of pediatric patients with CM-I, patients presenting with a syrinx who underwent expansile duraplasty with obex exploration had a significantly greater likelihood of syrinx and symptom resolution, without increased risk of CSF-related complications, compared to those who underwent bone-only decompression.

PMID: 33126216 [PubMed - as supplied by publisher]

Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.

J Immunother Cancer. 2020 Oct;8(2):

Authors: Brempelis KJ, Cowan CM, Kreuser SA, Labadie KP, Prieskorn BM, Lieberman NAP, Ene CI, Moyes KW, Chinn H, DeGolier KR, Matsumoto LR, Daniel SK, Yokoyama JK, Davis AD, Hoglund VJ, Smythe KS, Balcaitis SD, Jensen MC, Ellenbogen RG, Campbell JS, Pierce RH, Holland EC, Pillarisetty VG, Crane CA

Abstract
BACKGROUND: Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.
METHODS: Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.
RESULTS: Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.
CONCLUSIONS: Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.

PMID: 33115946 [PubMed - in process]

Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).

Transl Vis Sci Technol. 2020 Oct;9(11):19

Authors: Waldner DM, Ito K, Chen LL, Nguyen L, Chow RL, Lee A, Rancourt DE, Tremblay F, Stell WK, Bech-Hansen NT

Abstract
Purpose: Congenital stationary night blindness 2A (CSNB2A) is a genetic retinal disorder characterized by poor visual acuity, nystagmus, strabismus, and other signs of retinal dysfunction resulting from mutations in Cacna1f -the gene coding for the pore-forming subunit of the calcium channel CaV1.4. Mouse models of CSNB2A have shown that mutations causing the disease deleteriously affect photoreceptors and their synapses with second-order neurons. This study was undertaken to evaluate whether transgenic expression of Cacna1f could rescue morphology and visual function in a Cacna1f-KO model of CSNB2A.
Methods: Strategic creation, breeding and use of transgenic mouse lines allowed for Cre-driven retina-specific expression of Cacna1f in a CSNB2A model. Transgene expression and retinal morphology were investigated with immunohistochemistry in retinal wholemounts or cross-sections. Visual function was assessed by optokinetic response (OKR) analysis and electroretinography (ERG).
Results: Mosaic, prenatal expression of Cacna1f in the otherwise Cacna1f-KO retina was sufficient to rescue some visual function. Immunohistochemical analyses demonstrated wild-type-like photoreceptor and synaptic morphology in sections with transgenic expression of Cacna1f.
Conclusions: This report describes a novel system for Cre-inducible expression of Cacna1f in a Cacna1f-KO mouse model of CSNB2A and provides preclinical evidence for the potential use of gene therapy in the treatment of CSNB2A.
Translational Relevance: These data have relevance in the treatment of CSNB2A and in understanding how photoreceptor integration might be achieved in retinas in which photoreceptors have been lost, such as retinitis pigmentosa, age-related macular degeneration, and other degenerative conditions.

PMID: 33117610 [PubMed]

Healthcare utilization patterns among persons who use drugs during the COVID-19 pandemic.

J Subst Abuse Treat. 2021 02;121:108177

Authors: Murphy SM, Yoder J, Pathak J, Avery J

Abstract
Persons with drug use disorders are an underserved and stigmatized population, and the COVID-19 pandemic could exacerbate these issues. The discussion around those with drug use disorders in the midst of the pandemic has focused on the need to ensure uninterrupted treatment access; however, very few in this population actually receive treatment, and retention is a substantial issue among those who do. Evidence from other chronic conditions suggests persons at high risk for severe COVID-19 complications are foregoing care due to fear of contracting the virus. Persons with drug use disorders tend to fall into this high-risk category, and thus may be avoiding healthcare facilities. Our data suggest this is true. If so, adverse outcomes, and increased severity of use disorders and associated health complications, could become prevalent. Clinicians should identify persons with drug use disorders who may be foregoing treatment, and engage them using methods that minimize the risk of COVID-19 transmission.

PMID: 33109432 [PubMed - indexed for MEDLINE]

Satisfaction with life following mild traumatic brain injury: A TRACK-TBI Study.

J Neurotrauma. 2020 Oct 27;:

Authors: Agtarap SD, Campbell-Sills L, Jain S, Sun X, Dikmen S, Levin H, McCrea M, Mukherjee P, Nelson LD, Temkin N, Yuh EL, Giacino J, Manley GT, Investigators TT

Abstract
Identifying the principal determinants of life satisfaction following mild TBI (mTBI) may inform efforts to improve subjective well-being in this population. We examined life satisfaction among participants in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study who presented with mTBI (Glasgow Coma Scale=13-15; N=1,152). An L1-regularization path algorithm was used to select optimal sets of baseline and concurrent symptom measures for prediction of scores on the Satisfaction with Life Scale (SWLS) at 2 weeks and 3, 6, and 12 months post-injury. Multivariable linear regression models (ns=744-894) were then fit to evaluate associations between the empirically-selected predictors and SWLS scores at each follow-up visit. Results indicated that emotional post-TBI symptoms (b's= -1.27 to -0.77, ps<.05), anhedonia (b's = -1.59 to -1.08, ps<.01), and pain interference (b's= -1.38 to -0.89, ps<.001) contributed to the prediction of lower SWLS scores at all follow-ups. Insomnia predicted lower SWLS scores at 2 weeks, 3 months, and 6 months (b's= -1.11 to -0.83, ps<.01); and negative affect predicted lower SWLS scores at 2 weeks, 3 months, and 12 months (b's= -1.38 to -0.80, ps<.005). Other post-TBI symptom domains and baseline socio-demographic, injury-related, and clinical characteristics did not emerge as robust predictors of SWLS scores during the year after mTBI. Efforts to improve satisfaction with life following mTBI may benefit from a focus on the detection and treatment of affective symptoms, pain, and insomnia. The results reinforce the need for tailoring of evidence-based treatments for these conditions to maximize efficacy in patients with mTBI.

PMID: 33107371 [PubMed - as supplied by publisher]

Validity of the Brief Test of Adult Cognition by Telephone (BTACT) in Level 1 Trauma Center Patients 6 Months Post-Traumatic Brain Injury: A TRACK-TBI Study.

J Neurotrauma. 2020 Oct 27;:

Authors: Nelson LD, Barber J, Temkin N, Dams-O'Connor K, Dikmen S, Giacino J, Kramer MD, Levin H, McCrea M, Whyte J, Bodien YG, Yue JK, Manley GT

Abstract
Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1,422 TBI patients and 170 orthopedic trauma controls (OTC) from the multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6-months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising brief, phone-based cognitive screening tool for patients with TBI. While the BTACT's memory items appear to index verbal episodic memory, items that purport to assess executive functions may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

PMID: 33107388 [PubMed - as supplied by publisher]

The Temporal Relationship of Mental Health Problems and Functional Limitations following mTBI: A TRACK-TBI and TED Study.

J Neurotrauma. 2019 06;36(11):1786-1793

Authors: Zahniser E, Nelson LD, Dikmen SS, Machamer JE, Stein MB, Yuh E, Manley GT, Temkin NR, TRACK-TBI Investigators

Abstract
Mental health problems, such as depression and anxiety, are often associated with functional limitations after traumatic brain injury (TBI), prompting researchers to explore which of these TBI-related sequelae tends to precede the other. Past studies among patients with injuries ranging in severity have predominantly reported that functional impairments predict subsequent psychological concerns, rather than the other way around; however, it remains unclear whether this directionality holds for individuals with mild TBI (mTBI). The present study utilized a cross-lagged panel design within a structural equation modeling analytical framework to explore the longitudinal relationships of symptoms of depression and anxiety to functional status among 717 adult mTBI patients, with assessments occurring at 2 weeks and 3 months post-injury. Symptoms of both depression and anxiety significantly predicted subsequent functional limitations (λs = -0.21 and -0.25), whereas the reverse effects were nonsignificant (λs = -0.05 and -0.03); thus, psychological concerns appeared to function as a precursor to functional impairment. This pattern was particularly pronounced among patients with normal head computed tomography (CT) results; however, results were less clear cut among those subjects whose injuries were accompanied by intracranial abnormalities detected on CT imaging, suggesting the possibility of a more reciprocal relationship in the case of CT-positive mTBI. These results may serve to partially explain the incidence of persistent functional limitations observed among subsets of mTBI patients in past studies. Findings likewise highlight the importance of assessment and treatment for mental health problems after mTBI as an important factor to promote psychological well-being and functional recovery.

PMID: 30543138 [PubMed - indexed for MEDLINE]

Lemierre's syndrome treated operatively.

Proc (Bayl Univ Med Cent). 2020 Jun 23;33(4):671-673

Authors: Lanfear AT, Hamandi M, Fan J, Bolin ML, Williams M, DiMaio JM, Waters J

Abstract
Lemierre's syndrome (LS) is a pharyngeal infection complicated by infectious jugular vein thrombosis and septic emboli. Most commonly caused by Fusobacterium necrophorum, it may result in metastatic infection, especially when antibiotic treatment is delayed. Patients with LS are often healthy adults between 16 and 30 years who present with prolonged symptoms of pharyngitis, lateral neck pain, and fever. Other symptoms may include shortness of breath, tachycardia, and hypotension. When administered promptly, antibiotics can act as an effective treatment. However, complications may arise that require additional intervention. Herein, we report a case of LS in a young adult, complicated by severe pleural effusions that required surgical decortication.

PMID: 33100566 [PubMed]

Sutureless valve and rapid deployment valves: a systematic review and meta-analysis of comparative studies.

Ann Cardiothorac Surg. 2020 Sep;9(5):364-374

Authors: Flynn CD, Williams ML, Chakos A, Hirst L, Muston B, Tian DH

Abstract
Background: The treatment of aortic valve disease is the most common valvular surgery in industrialized nations, with 3-9% of the population over the age of eighty having at least moderate aortic stenosis. As transcatheter aortic valve replacement (TAVR) has become more established, newer surgical prostheses have been developed with a variety of anchoring systems that do not rely solely on sutures to hold the valve in an appropriate position. The Edwards Intuity valve is a bovine pericardial prosthesis that is modelled on the widely implanted Perimount MagnaEase aortic prosthesis. The Perceval valve is a bovine pericardial valve attached to a self-expanding nitinol stent, which uses the radial force exerted on the patient's aortic annulus and aortic root by the stent portion to hold the valve in position. This meta-analysis compares the outcomes of comparative studies of these two valve systems.
Methods: This systematic review and meta-analysis compares the outcomes of rapid deployment valves (RDV) and sutureless valves (SURD) and was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and guidance. The search strategy interrogated six electronic databases. Outcomes measured included all-cause mortality at latest follow up, stroke, cross-clamp and cardiopulmonary bypass (CPB) times, pacemaker implantation rates, paravalvular leak and post-operative transvalvular gradient.
Results: The search strategy identified 407 unique papers for initial assessment with seven studies qualifying for inclusion in the analysis. The outcomes of 4,076 patients (1,650 RDV, 2,426 SURD) were included. There was no difference in mortality, stroke or moderate or worse paravalvular regurgitation between the two groups. SURD had significantly shorter CPB time by 15.7 minutes [95% confidence interval (CI): 4.2-27.1; P=0.007] and a shorter cross-clamp time by 11.3 minutes (95% CI: 6.3-16.3; P<0.001) compared to RDV. RDV had a lower post-operative transvalvular gradient by 2.5 mmHg (95% CI: 1.2-3.8; P<0.001) and a lower rate of mild paravalvular regurgitation (OR 2.51; 95% CI: 1.435-4.768; P=0.004).
Conclusions: Both valve types have an adequate safety profile and are comparable to conventional sutured prostheses. There was a significant reduction in cross-clamp and CPB times associated with SURD. This may be of benefit for patients requiring multiple concomitant procedures and increases the utility of minimally invasive valve replacement. However, SURD was associated with higher post-operative transvalvular gradients and a higher incidence of paravalvular regurgitation.

PMID: 33102175 [PubMed]

Estimating minimal clinically important differences for two scales in patients with chronic traumatic brain injury.

Curr Med Res Opin. 2020 Oct 23;:1

Authors: Mattke S, Cramer SC, Wang M, Bettger JP, Cockroft KM, Feng W, Jaffee M, Oyesanya TO, Puccio AM, Temkin N, Winstein C, Wolf SL, Yochelson MR

Abstract
Background: This study aimed to establish the minimal clinically important difference (MCID) for the Fugl-Meyer Motor Scale (FMMS) and the Disability Rating Scale (DRS) to evaluate interventions in patients with motor deficits in the chronic phase after traumatic brain injury (TBI). Methods: MCIDs were established with a structured expert consultation process, the RAND/UCLA modified Delphi method. This process consisted of a literature review and input from a 10-person, multidisciplinary expert panel. The experts were asked to rate meaningfulness of improvements in hypothetical patients and numeric changes via two rounds of ratings and an in-person meeting. Results: The estimated MCIDs were six and five points on the FMMS Upper and Lower Extremity Scale, respectively, and one point on the DRS. The experts argued against establishing an MCID for the combined FMMS because the same change was more likely to be meaningful if concentrated in one extremity and because a meaningful improvement in one extremity implies meaningfulness irrespective of the changes in the other. Conclusions: This study is the first to establish MCIDs for the FMMS and the DRS in the chronic phase after TBI. The results may be helpful for the design and interpretation of clinical trials of interventions.

PMID: 33095678 [PubMed - as supplied by publisher]

Meta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes.

EBioMedicine. 2020 Oct 20;61:103062

Authors: Bowker N, Shah RL, Sharp SJ, Luan J, Stewart ID, Wheeler E, Ferreira MAR, Baras A, Wareham NJ, Langenberg C, Lotta LA

Abstract
BACKGROUND: Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D.
METHODS: We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls.
FINDINGS: In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10-12). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10-7). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D.
INTERPRETATION: Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small.
FUNDING: The EPICNorfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).

PMID: 33096487 [PubMed - as supplied by publisher]

The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions.

Physiology (Bethesda). 2020 Nov 01;35(6):375-390

Authors: Ramirez JM, Karlen-Amarante M, Wang JJ, Bush NE, Carroll MS, Weese-Mayer DE, Huff A

Abstract
Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stress-an important driver of the clinical presentation of RTT.

PMID: 33052774 [PubMed - in process]