UW Neurological Surgery Recent PubMed Publications

Comparison of full-endoscopic and minimally invasive decompression for lumbar spinal stenosis in the setting of degenerative scoliosis and spondylolisthesis.

Neurosurg Focus. 2019 05 01;46(5):E16

Authors: Hasan S, McGrath LB, Sen RD, Barber JK, Hofstetter CP

Abstract
OBJECTIVEThe management of lumbar spinal stenosis (LSS) with concurrent scoliosis and/or spondylolisthesis remains controversial. Full-endoscopic unilateral laminotomy for bilateral decompression (ULBD) facilitates neural decompression while preserving stabilizing osseoligamentous structures and may be uniquely suited for the treatment of LSS with concurrent mild to moderate degenerative deformity. The safety and efficacy of full-endoscopic versus minimally invasive surgery (MIS) ULBD in this patient population is studied here for the first time.METHODSA retrospective analysis of prospectively collected data was conducted on 45 consecutive LSS patients with concurrent scoliosis (≥ 10° coronal Cobb angle) and/or spondylolisthesis (≥ 3 mm). Patient demographics, operative details, complications, and imaging characteristics were reviewed. Outcomes were quantified using back and leg visual analog scale (VAS) scores and the Oswestry Disability Index (ODI) at 2 weeks, 3 months, and 1 year.RESULTSA total of 26 patients underwent full-endoscopic and 19 underwent MIS-ULBD with an average follow-up period of 12 months. The endoscopic cohort experienced a significantly shorter hospital length of stay (p = 0.014) and fewer adverse events (p = 0.010). Both cohorts experienced significant improvements in VAS and ODI scores at all time points (p < 0.001), but the endoscopic cohort demonstrated significantly better early ODI scores (p = 0.024).CONCLUSIONSEndoscopic and MIS-ULBD result in similar functional outcomes for LSS with mild to moderate deformity, while the endoscopic approach demonstrates a favorable rate of complications. Further studies are required to better delineate the characteristics of spinal deformities amenable to this approach and the durability of functional results.

PMID: 31042656 [PubMed - indexed for MEDLINE]

Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis.

Sci Transl Med. 2019 05 01;11(490):

Authors: Williams MR, Costa SK, Zaramela LS, Khalil S, Todd DA, Winter HL, Sanford JA, O'Neill AM, Liggins MC, Nakatsuji T, Cech NB, Cheung AL, Zengler K, Horswill AR, Gallo RL

Abstract
Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides' capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus-mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.

PMID: 31043573 [PubMed - indexed for MEDLINE]

Carcinoid tumor of lung and BRCA mutation: a case report.

J Med Case Rep. 2019 May 01;13(1):132

Authors: Shariff MZ, Curras-Martin D, Campbell N, Gupta V, Mikhail JD, Levitt MJ, Hossain MA

Abstract
BACKGROUND: A BRCA mutation is a mutation in either of the BRCA1 or BRCA2 genes, which are tumor suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, whereas others have no proven impact. BRCA mutations are well known to be associated with breast, uterine, and ovarian cancers along with some nongynecological malignancies involving the peritoneum, prostate, pancreas, skin, stomach, and rectum. However, there are no reported cases to date of an association between carcinoid tumors and a BRCA mutation.
CASE PRESENTATION: Our patient was a 33-year-old White woman with BRCA2 mutation who presented to her primary care physician for evaluation of abdominal pain. She underwent computed tomography of her abdomen and pelvis, which showed an incidental finding of infrahilar mass along with renal stones. Further workup with bronchoscopy and biopsy of the mass confirmed it to be a carcinoid tumor of the lung.
CONCLUSIONS: No literature thus far exists describing a connection between BRCA mutations and carcinoid tumors. Early diagnosis and prompt treatment of carcinoid tumors are proven to have impact on survival and prognosis of these patients.

PMID: 31039815 [PubMed - indexed for MEDLINE]

A case report of an unruptured tectal AVM presenting with obstructive hydrocephalus that resolved upon spontaneous obliteration of the venous varix.

J Clin Neurosci. 2019 Jul;65:157-160

Authors: Bass DI, Walker M, Ferreira M, Ghodke B

Abstract
Cerebral arteriovenous malformations (AVMs) are complicated lesions representing a wide spectrum of pathology. They are frequently associated arterial aneurysms and venous varices, the latter of which carry a particularly high risk of rupture. AVM rupture commonly results in hydrocephalus, but there are a rare number of cases in which hydrocephalus develops as a result of an unruptured AVM. An elderly woman with a benign medical history presented to an outside hospital with 5 days of progressively worsening headaches that she described as retroorbital, dull, and lateralizing to the right. Workup at an outside hospital with a brain magnetic resonance image (MRI) and a head computed tomography angiogram (CTA) revealed concern for a tectal AVM with an associated venous varix abutting the tectal plate. Four weeks later, her headaches and diplopia had significantly improved. A diagnostic cerebral angiogram revealed that venous varix had decreased in size and a subsequent CTA showed interval improvement of her hydrocephalus. By the following month, her clinical signs and symptoms had completely resolved. Resolution of the patient's symptoms clearly correlated with multiple radiographic findings, and therefore it seems reasonable to assume that expansion of the varix was the inciting event that lead to the development of her symptoms. Although this case reflects an exceptional series of events, it helps emphasize the point that a shunt or a ventriculostomy may not be necessary in a patient presenting with hydrocephalus from an unruptured AVM.

PMID: 31036505 [PubMed - indexed for MEDLINE]

Primary External Ventricular Drainage Catheter Versus Intraparenchymal ICP Monitoring: Outcome Analysis.

Neurocrit Care. 2019 08;31(1):11-21

Authors: Bales JW, Bonow RH, Buckley RT, Barber J, Temkin N, Chesnut RM

Abstract
BACKGROUND: Intracranial pressure (ICP) monitoring is central to the care of severe traumatic brain injury (TBI). External ventricular drains (EVD) allow ICP control via cerebrospinal fluid drainage, whereas intraparenchymal monitors (IPM) for ICP do not, but it is unclear whether EVD placement improves outcomes. To evaluate whether there exists a difference in patient outcomes with the use of EVD versus IPM in severe TBI patients, we conducted a retrospective cohort study using data from the Citicoline Brain Injury Treatment trial.
METHODS: Adults with Glasgow Coma Score < 9 who had either an EVD or IPM placed within 6 h of study center arrival were included. We compared patients with EVD placement to those without on Glasgow Outcome Scale-Extended (GOS-E) and neuropsychological performance at 180 days, mortality, and intensive care unit length of stay. We used regression models with propensity score weighting for probability of EVD placement to test for association between EVD use and outcomes. Of 224 patients included, 45% received an EVD.
RESULTS: EVD patients had lower GOS-E at 180 days [3.8 ± 2.2 vs 4.9 ± 2.2, p = 0.002; weighted difference - 0.97, 95% CI (- 1.58, - 0.37)], higher in-hospital mortality [23% vs 10%, p = 0.014; weighted OR 2.46, 95% CI (1.20, 5.05)], and did significantly worse on all 8 neuropsychological measures. Additional sensitivity analysis was performed to minimize confounding effects supported our initial results.
CONCLUSIONS: Our retrospective data analysis suggests that early placement of EVDs in severe TBI is associated with worse functional and neuropsychological outcomes and higher mortality than IPMs and future prospective trials are needed to determine whether these results represent an important consideration for clinicians.

PMID: 31037639 [PubMed - indexed for MEDLINE]

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

Am J Hum Genet. 2019 05 02;104(5):968-976

Authors: Karasozen Y, Osbun JW, Parada CA, Busald T, Tatman P, Gonzalez-Cuyar LF, Hale CJ, Alcantara D, O'Driscoll M, Dobyns WB, Murray M, Kim LJ, Byers P, Dorschner MO, Ferreira M

Abstract
The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.

PMID: 31031011 [PubMed - indexed for MEDLINE]

Beyond Blood Smears: Qualification of Plasmodium 18S rRNA as a Biomarker for Controlled Human Malaria Infections.

Am J Trop Med Hyg. 2019 06;100(6):1466-1476

Authors: Seilie AM, Chang M, Hanron AE, Billman ZP, Stone BC, Zhou K, Olsen TM, Daza G, Ortega J, Cruz KR, Smith N, Healy SA, Neal J, Wallis CK, Shelton L, Mankowski TV, Wong-Madden S, Mikolajczak SA, Vaughan AM, Kappe SHI, Fishbaugher M, Betz W, Kennedy M, Hume JCC, Talley AK, Hoffman SL, Chakravarty S, Sim BKL, Richie TL, Wald A, Plowe CV, Lyke KE, Adams M, Fahle GA, Cowan EP, Duffy PE, Kublin JG, Murphy SC

Abstract
18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites that used blood smears and Plasmodium 18S rRNA/rDNA biomarker nucleic acid tests (NATs) for time to positivity. We validated a multiplex quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for Plasmodium 18S rRNA, prospectively compared blood smears and qRT-PCR for three trials, and modeled treatment effects at different biomarker-defined parasite densities to assess the impact on infection detection, symptom reduction, and measured intervention efficacy. Literature review demonstrated accelerated NAT-based infection detection compared with blood smears (mean acceleration: 3.2-3.6 days). For prospectively tested trials, the validated Plasmodium 18S rRNA qRT-PCR positivity was earlier (7.6 days; 95% CI: 7.1-8.1 days) than blood smears (11.0 days; 95% CI: 10.3-11.8 days) and significantly preceded the onset of grade 2 malaria-related symptoms (12.2 days; 95% CI: 10.6-13.3 days). Discrepant analysis showed that the risk of a blood smear-positive, biomarker-negative result was negligible. Data modeling predicted that treatment triggered by specific biomarker-defined thresholds can differentiate complete, partial, and non-protective outcomes and eliminate many grade 2 and most grade 3 malaria-related symptoms post-CHMI. Plasmodium 18S rRNA is a sensitive and specific biomarker that can justifiably replace blood smears for infection detection in CHMI trials in non-endemic settings. This study led to biomarker qualification through the U.S. Food and Drug Administration for use in CHMI studies at non-endemic sites, which will facilitate biomarker use for the qualified context of use in drug and vaccine trials.

PMID: 31017084 [PubMed - indexed for MEDLINE]

Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation.

Cell Rep. 2019 04 23;27(4):1165-1175.e5

Authors: de Oliveira Mann CC, Orzalli MH, King DS, Kagan JC, Lee ASY, Kranzusch PJ

Abstract
Stimulator of interferon genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here, we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.

PMID: 31018131 [PubMed - indexed for MEDLINE]

Re: Understanding quality of life impact in people with retinal vein occlusion: a qualitative inquiry.

Clin Exp Optom. 2019 09;102(5):536

Authors: Monaghan MT, Steenson C, Williams MA

PMID: 31018248 [PubMed - indexed for MEDLINE]

In Memoriam: John H. Bond, MD (1940-2018).

Gastrointest Endosc. 2019 May;89(5):911-912

Authors: Levitt MD, Shaukat A

PMID: 31005131 [PubMed - in process]

Spontaneous Variation in Electrocorticographic Resting-State Connectivity.

Brain Connect. 2019 07;9(6):488-499

Authors: Casimo K, Madhyastha TM, Ko AL, Brown AB, Grassia F, Ojemann JG, Weaver KE

Abstract
Prior studies using functional magnetic resonance imaging, electroencephalography, and magnetoencephalography have observed both structured patterns in resting-state functional connectivity and spontaneous longitudinal variation in connectivity patterns independent of a task. In this first study using electrocorticography (ECoG), we characterized spontaneous, intersession variation in resting-state functional connectivity not linked to a task. We evaluated pairwise connectivity between electrodes using three measures (phase locking value [PLV], amplitude correlation, and coherence) for six canonical frequency bands, capturing different characteristics of time-evolving signals. We grouped electrodes into 10 functional regions and used intraclass correlation (ICC) to estimate pairwise longitudinal stability. We found that stronger PLV (PLV ≥0.4) in theta through gamma bands and strong correlation in all bands (R2's ≥0.6) are linked to substantial stability (ICC ≥0.6), but that stability does not imply strong phase locking or amplitude correlation. There was no notable link between strong coherence and high ICC. All within-region PLVs are markedly stable across frequencies. In addition, we highlight interaction patterns across several regions: parahippocampal/entorhinal cortex is characterized by stable, weak functional connectivity except self-connections. Dorsolateral prefrontal cortex connectivity is weak and unstable, except self-connections. Inferior parietal lobule has little stability despite narrow connectivity bounds. We confirm prior studies linking functional connectivity strength and intersession variability, extending into higher frequencies than other modalities, with greater spatial specificity than scalp electrophysiology. We suggest further studies quantitatively compare ECoG to other modalities and/or use these findings as a baseline to capture functional connectivity and dynamics linked to perturbations with a task or disease state.

PMID: 31002014 [PubMed - indexed for MEDLINE]

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

Nat Genet. 2018 01;50(1):42-53

Authors: Demenais F, Margaritte-Jeannin P, Barnes KC, Cookson WOC, Altmüller J, Ang W, Barr RG, Beaty TH, Becker AB, Beilby J, Bisgaard H, Bjornsdottir US, Bleecker E, Bønnelykke K, Boomsma DI, Bouzigon E, Brightling CE, Brossard M, Brusselle GG, Burchard E, Burkart KM, Bush A, Chan-Yeung M, Chung KF, Couto Alves A, Curtin JA, Custovic A, Daley D, de Jongste JC, Del-Rio-Navarro BE, Donohue KM, Duijts L, Eng C, Eriksson JG, Farrall M, Fedorova Y, Feenstra B, Ferreira MA, Australian Asthma Genetics Consortium (AAGC) collaborators, Freidin MB, Gajdos Z, Gauderman J, Gehring U, Geller F, Genuneit J, Gharib SA, Gilliland F, Granell R, Graves PE, Gudbjartsson DF, Haahtela T, Heckbert SR, Heederik D, Heinrich J, Heliövaara M, Henderson J, Himes BE, Hirose H, Hirschhorn JN, Hofman A, Holt P, Hottenga J, Hudson TJ, Hui J, Imboden M, Ivanov V, Jaddoe VWV, James A, Janson C, Jarvelin MR, Jarvis D, Jones G, Jonsdottir I, Jousilahti P, Kabesch M, Kähönen M, Kantor DB, Karunas AS, Khusnutdinova E, Koppelman GH, Kozyrskyj AL, Kreiner E, Kubo M, Kumar R, Kumar A, Kuokkanen M, Lahousse L, Laitinen T, Laprise C, Lathrop M, Lau S, Lee YA, Lehtimäki T, Letort S, Levin AM, Li G, Liang L, Loehr LR, London SJ, Loth DW, Manichaikul A, Marenholz I, Martinez FJ, Matheson MC, Mathias RA, Matsumoto K, Mbarek H, McArdle WL, Melbye M, Melén E, Meyers D, Michel S, Mohamdi H, Musk AW, Myers RA, Nieuwenhuis MAE, Noguchi E, O'Connor GT, Ogorodova LM, Palmer CD, Palotie A, Park JE, Pennell CE, Pershagen G, Polonikov A, Postma DS, Probst-Hensch N, Puzyrev VP, Raby BA, Raitakari OT, Ramasamy A, Rich SS, Robertson CF, Romieu I, Salam MT, Salomaa V, Schlünssen V, Scott R, Selivanova PA, Sigsgaard T, Simpson A, Siroux V, Smith LJ, Solodilova M, Standl M, Stefansson K, Strachan DP, Stricker BH, Takahashi A, Thompson PJ, Thorleifsson G, Thorsteinsdottir U, Tiesler CMT, Torgerson DG, Tsunoda T, Uitterlinden AG, van der Valk RJP, Vaysse A, Vedantam S, von Berg A, von Mutius E, Vonk JM, Waage J, Wareham NJ, Weiss ST, White WB, Wickman M, Widén E, Willemsen G, Williams LK, Wouters IM, Yang JJ, Zhao JH, Moffatt MF, Ober C, Nicolae DL

Abstract
We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

PMID: 29273806 [PubMed - indexed for MEDLINE]

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Nat Commun. 2019 04 15;10(1):1741

Authors: Ferreira MA, Gamazon ER, Al-Ejeh F, Aittomäki K, Andrulis IL, Anton-Culver H, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Azzollini J, Balmaña J, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska K, Blomqvist C, Bogdanova NV, Bojesen SE, Bolla MK, Borg A, Brauch H, Brenner H, Broeks A, Burwinkel B, Caldés T, Caligo MA, Campa D, Campbell I, Canzian F, Carter J, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Christiansen H, Chung WK, Claes KBM, Clarke CL, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, Dennis J, Devilee P, Diez O, Dörk T, Dunning AM, Dwek M, Eccles DM, Ejlertsen B, Ellberg C, Engel C, Eriksson M, Fasching PA, Fletcher O, Flyger H, Friedman E, Frost D, Gabrielson M, Gago-Dominguez M, Ganz PA, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hamann U, He W, Heyworth J, Hogervorst FBL, Hollestelle A, Hoover RN, Hopper JL, Hulick PJ, Humphreys K, Imyanitov EN, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs C, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Joseph V, Karlan BY, Khusnutdinova E, Kiiski JI, Ko YD, Jones ME, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leslie G, Lester J, Lesueur F, Lindström S, Long J, Loud JT, Lubiński J, Makalic E, Mannermaa A, Manoochehri M, Margolin S, Maurer T, Mavroudis D, McGuffog L, Meindl A, Menon U, Michailidou K, Miller A, Montagna M, Moreno F, Moserle L, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Pharoah PDP, Plaseska-Karanfilska D, Poppe B, Presneau N, Radice P, Rantala J, Rennert G, Risch HA, Saloustros E, Sanden K, Sawyer EJ, Schmidt MK, Schmutzler RK, Sharma P, Shu XO, Simard J, Singer CF, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne K, Thull DL, Tischkowitz M, Toland AE, Torres D, Truong T, Tung N, Vachon CM, van Asperen CJ, van den Ouweland AMW, van Rensburg EJ, Vega A, Viel A, Wang Q, Wappenschmidt B, Weitzel JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Kraft P, Antoniou AC, Zheng W, Easton DF, Milne RL, Beesley J, Chenevix-Trench G

Abstract
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

PMID: 30988301 [PubMed - indexed for MEDLINE]

Colour profile analysis of Port wines by various instrumental and visual methods.

J Sci Food Agric. 2019 May;99(7):3563-3571

Authors: Soares-da-Silva FA, Campos FM, Ferreira ML, Ribeiro N, Amaral B, Simões T, Silva CL

Abstract
BACKGROUND: Wine colour is an important quality parameter, being the first sensorial attribute evaluated during wine tasting. The perception of wine colour can be different depending on many factors, including the depth of the sample under observation. The main objectives of the present study were to measure the colour of Port wines using CIE L*, a*, b* parameters at different depths with various instrumental techniques (spectrophotometry and colorimetry), and to compare the obtained results with the sensory (visual) perception of colour samples.
RESULTS: Representative profiles of lightness (L*), hue (H*) and chroma (C*) at different depths were obtained using Port wine samples from various categories and ages. In general, relatively good correlations between the colorimetric and spectrophotometric methods were obtained for the L* and H* parameters. The results of the sensory tests also showed good correlations between the visually assessed hue scores and the colorimetric measurements of the H* parameter, particularly at the lower depths tested (up to 4.0 mm).
CONCLUSIONS: Overall, the results indicate that the colorimetric method can be used for estimating wine colour parameters, providing useful information about the colour profile of wines at different depths. © 2019 Society of Chemical Industry.

PMID: 30628078 [PubMed - indexed for MEDLINE]

Associations between lung and endothelial function in early middle age.

Respirology. 2020 01;25(1):89-96

Authors: Hancox RJ, Thomas L, Williams MJA, Sears MR

Abstract
BACKGROUND AND OBJECTIVE: Chronic lung disease is associated with impaired endothelial function and this may be a risk factor for poor cardiovascular health. It is unknown if there is an association between lung and endothelial function in the general population. We investigated associations between lung and endothelial function in a population-based cohort of 38-year-old men and women.
METHODS: Systemic endothelial function was measured using peripheral arterial tonometry to calculate the Framingham reactive hyperaemia index. Lung function was assessed using spirometry, plethysmographic lung volumes, airway conductance and gas transfer. Associations between lung and endothelial function were assessed with and without adjustment for potential confounding factors using regression analyses.
RESULTS: Sex modified the association between lung and endothelial function. Among women, lower values of pre- and post-bronchodilator spirometry, total lung capacity and functional residual capacity (FRC) were associated with worse endothelial function (P < 0.05). These associations persisted after adjustment for smoking, asthma diagnoses, fitness and body mass index. Associations were weaker among men: only FRC, airway conductance and post-bronchodilator forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) ratios were associated with endothelial function. Endothelial function was not associated with gas transfer in either sex.
CONCLUSION: Lower lung volumes and airflow obstruction are associated with endothelial dysfunction among women. There is weaker evidence for an association between airway and endothelial function in men. These findings may partly explain the increased risk of cardiovascular disease among people with poor lung function, but suggest that there are sex differences in this association.

PMID: 30985946 [PubMed - indexed for MEDLINE]

Biodentine™ Boosts, WhiteProRoot®MTA Increases and Life® Suppresses Odontoblast Activity.

Materials (Basel). 2019 Apr 11;12(7):

Authors: Paula A, Laranjo M, Marto CM, Abrantes AM, Casalta-Lopes J, Gonçalves AC, Sarmento-Ribeiro AB, Ferreira MM, Botelho MF, Carrilho E

Abstract
(1) Background: When pulp exposure occurs, reparative dentinogenesis can be induced by direct pulp capping to maintain the vitality and function of the tissue. The aim of this work was to assess the cytotoxicity and bioactivity of three different direct pulp capping materials, calcium hydroxide (Life®), mineral trioxide aggregate (WhiteProRoot®MTA) and calcium silicate (Biodentine™), in an odontoblast-like mouse cell line (MDPC-23). (2) Methods: Metabolic activity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT)assay, viability by the sulforhodamine B (SRB) assay, and the type of death and cell cycle analysis by flow cytometry. Alkaline phosphatase was evaluated by polymerase chain reaction (PCR), and dentin sialoprotein expression was assessed by immunocytochemistry. Mineralization was determined by the Alizarin Red S colorimetric assay and quantified by spectrophotometry. (3) Results: Life® induced a decrease in metabolic activity and viability, which is associated with an increase cell death. WhiteProRoot®MTA and Biodentine™ induced similar effects in cytotoxicity assays, with an increase in the expression of dentin sialoprotein (DSP) and formation of mineralized deposits, especially with Biodentine™. (4) Conclusions: The results of WhiteProRoot®MTA confirm its indication for these therapies, justifying its recognition as the "gold standard". Biodentine™ may be an alternative, since they promote the same cellular response that mineral trioxide aggregate (MTA) does.

PMID: 30978943 [PubMed]

Genetic correlates of wall shear stress in a patient-specific 3D-printed cerebral aneurysm model.

J Neurointerv Surg. 2019 Oct;11(10):999-1003

Authors: Levitt MR, Mandrycky C, Abel A, Kelly CM, Levy S, Chivukula VK, Zheng Y, Aliseda A, Kim LJ

Abstract
OBJECTIVES: To study the correlation between wall shear stress and endothelial cell expression in a patient-specific, three-dimensional (3D)-printed model of a cerebral aneurysm.
MATERIALS AND METHODS: A 3D-printed model of a cerebral aneurysm was created from a patient's angiogram. After populating the model with human endothelial cells, it was exposed to media under flow for 24 hours. Endothelial cell morphology was characterized in five regions of the 3D-printed model using confocal microscopy. Endothelial cells were then harvested from distinct regions of the 3D-printed model for mRNA collection and gene analysis via quantitative polymerase chain reaction (qPCR.) Cell morphology and mRNA measurement were correlated with computational fluid dynamics simulations.
RESULTS: The model was successfully populated with endothelial cells, which survived under flow for 24 hours. Endothelial morphology showed alignment with flow in the proximal and distal parent vessel and aneurysm neck, but disorganization in the aneurysm dome. Genetic analysis of endothelial mRNA expression in the aneurysm dome and distal parent vessel was compared with the proximal parent vessels. ADAMTS-1 and NOS3 were downregulated in the aneurysm dome, while GJA4 was upregulated in the distal parent vessel. Disorganized morphology and decreased ADAMTS-1 and NOS3 expression correlated with areas of substantially lower wall shear stress and wall shear stress gradient in computational fluid dynamics simulations.
CONCLUSIONS: Creating 3D-printed models of patient-specific cerebral aneurysms populated with human endothelial cells is feasible. Analysis of these cells after exposure to flow demonstrates differences in both cell morphology and genetic expression, which correlate with areas of differential hemodynamic stress.

PMID: 30979845 [PubMed - indexed for MEDLINE]

A randomized controlled trial of WATAAP to promote physical activity in colorectal and endometrial cancer survivors.

Psychooncology. 2019 07;28(7):1420-1429

Authors: Maxwell-Smith C, Hince D, Cohen PA, Bulsara MK, Boyle T, Platell C, Tan P, Levitt M, Salama P, Tan J, Salfinger S, Makin G, Mohan GRKA, Jiménez-Castuera R, Hardcastle SJ

Abstract
OBJECTIVE: The objective of this study was to ascertain whether wearable technology coupled with action planning was effective in increasing physical activity (PA) in colorectal and endometrial cancer survivors at cardiovascular risk.
METHODS: Sixty-eight survivors who had cardiovascular risk factors and were insufficiently active were randomized to intervention and control arms. Intervention participants were given a wearable tracker for 12 weeks, two group sessions, and a support phone call. Participants in the control arm received print materials describing PA guidelines. Assessments at baseline and 12 weeks measured triaxial and uniaxial estimates of moderate-vigorous physical activity (MVPA), sedentary behaviour, blood pressure, and body mass index (BMI).
RESULTS: The intervention group significantly increased MVPA by 45 min/wk compared with a reduction of 21 min/wk in the control group. Group by time interactions were significant for minutes of MVPA (F1,126  = 5.14, P = 0.025). For those with diastolic hypertension, there was a significant group by time interaction (F1,66  = 4.89, P = 0.031) with a net reduction of 9.89 mm Hg in the intervention group.
CONCLUSIONS: Significant improvements in MVPA were observed following the intervention. The results display promise for the use of pragmatic, low-intensity interventions using wearable technology.

PMID: 30980691 [PubMed - indexed for MEDLINE]

Current state of transfusion in traumatic brain injury and associated coagulopathy.

Transfusion. 2019 04;59(S2):1522-1528

Authors: Stolla M, Zhang F, Meyer MR, Zhang J, Dong JF

Abstract
Traumatic brain injury (TBI)-induced coagulopathy has long been recognized as a significant risk for poor outcomes in patients with TBI, but its pathogenesis remains poorly understood. As a result, current treatment options for the condition are limited and ineffective. The lack of information is most significant for the impact of blood transfusions on patients with isolated TBI and in the absence of confounding influences from trauma to the body and limbs and the resultant hemorrhagic shock. Here we discuss recent progress in understanding the pathogenesis of TBI-induced coagulopathy and the current state of blood transfusions for patients with TBI and associated coagulopathy.

PMID: 30980753 [PubMed - indexed for MEDLINE]

A Randomized Trial Evaluating the Prophylactic Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation.

J Infect Dis. 2018 02 14;217(5):693-702

Authors: Murphy SC, Duke ER, Shipman KJ, Jensen RL, Fong Y, Ferguson S, Janes HE, Gillespie K, Seilie AM, Hanron AE, Rinn L, Fishbaugher M, VonGoedert T, Fritzen E, Kappe SH, Chang M, Sousa JC, Marcsisin SR, Chalon S, Duparc S, Kerr N, Möhrle JJ, Andenmatten N, Rueckle T, Kublin JG

Abstract
Background: DSM265 is a selective inhibitor of Plasmodium dihydroorotate dehydrogenase that fully protected against controlled human malarial infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites when administered 1 day before challenge and provided partial protection when administered 7 days before challenge.
Methods: A double-blinded, randomized, placebo-controlled trial was performed to assess safety, tolerability, pharmacokinetics, and efficacy of 1 oral dose of 400 mg of DSM265 before CHMI. Three cohorts were studied, with DSM265 administered 3 or 7 days before direct venous inoculation of sporozoites or 7 days before 5 bites from infected mosquitoes.
Results: DSM265-related adverse events consisted of mild-to-moderate headache and gastrointestinal symptoms. DSM265 concentrations were consistent with pharmacokinetic models (mean area under the curve extrapolated to infinity, 1707 µg*h/mL). Placebo-treated participants became positive by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and were treated 7-10 days after CHMI. Among DSM265-treated subjects, 2 of 6 in each cohort were sterilely protected. DSM265-treated recipients had longer times to development of parasitemia than placebo-treated participants (P < .004).
Conclusions: This was the first CHMI study of a novel antimalarial compound to compare direct venous inoculation of sporozoites and mosquito bites. Times to qRT-PCR positivity and treatment were comparable for both routes. DSM265 given 3 or 7 days before CHMI was safe and well tolerated but sterilely protected only one third of participants.

PMID: 29216395 [PubMed - indexed for MEDLINE]