UW Neurological Surgery Recent PubMed Publications

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.

J Natl Cancer Inst. 2019 08 01;111(8):782-794

Authors: Janssen QP, Buettner S, Suker M, Beumer BR, Addeo P, Bachellier P, Bahary N, Bekaii-Saab T, Bali MA, Besselink MG, Boone BA, Chau I, Clarke S, Dillhoff M, El-Rayes BF, Frakes JM, Grose D, Hosein PJ, Jamieson NB, Javed AA, Khan K, Kim KP, Kim SC, Kim SS, Ko AH, Lacy J, Margonis GA, McCarter MD, McKay CJ, Mellon EA, Moorcraft SY, Okada KI, Paniccia A, Parikh PJ, Peters NA, Rabl H, Samra J, Tinchon C, van Tienhoven G, van Veldhuisen E, Wang-Gillam A, Weiss MJ, Wilmink JW, Yamaue H, Homs MYV, van Eijck CHJ, Katz MHG, Groot Koerkamp B

Abstract
BACKGROUND: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.
METHODS: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.
RESULTS: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX.
CONCLUSIONS: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

PMID: 31086963 [PubMed - indexed for MEDLINE]

Unsupervised determination of protein crystal structures.

Proc Natl Acad Sci U S A. 2019 05 28;116(22):10813-10818

Authors: Ufimtsev IS, Levitt M

Abstract
We present a method for automatic solution of protein crystal structures. The method proceeds with a single initial model obtained, for instance, by molecular replacement (MR). If a good-quality search model is not available, as often is the case with MR of distant homologs, our method first can automatically screen a large pool of poorly placed models and single out promising candidates for further processing if there are any. We demonstrate its utility by solving a set of synthetic cases in the 2.9- to 3.45-Å resolution.

PMID: 31088963 [PubMed - indexed for MEDLINE]

Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination.

Proc Natl Acad Sci U S A. 2019 05 28;116(22):10819-10823

Authors: Ufimtsev IS, Almagor L, Weis WI, Levitt M

Abstract
In the companion paper by Ufimtsev and Levitt [Ufimtsev IS, Levitt M (2019) Proc Natl Acad Sci USA, 10.1073/pnas.1821512116], we presented a method for unsupervised solution of protein crystal structures and demonstrated its utility by solving several test cases of known structure in the 2.9- to 3.45-Å resolution range. Here we apply this method to solve the crystal structure of a 966-amino acid construct of human lethal giant larvae protein (Lgl2) that resisted years of structure determination efforts, at 3.2-Å resolution. The structure was determined starting with a molecular replacement (MR) model identified by unsupervised refinement of a pool of 50 candidate MR models. This initial model had 2.8-Å RMSD from the solution. The solved structure was validated by comparison with a model subsequently derived from an alternative crystal form diffracting to higher resolution. This model could phase an anomalous difference Fourier map from an Hg derivative, and a single-wavelength anomalous dispersion phased density map made from these sites aligned with the refined structure.

PMID: 31088964 [PubMed - indexed for MEDLINE]

Long-term outcomes of surgical management of rectal prolapse.

ANZ J Surg. 2019 May 13;:

Authors: Ng ZQ, Levitt M, Tan P, Makin G, Platell C

Abstract
BACKGROUND: Various surgical options for rectal prolapse are available but none have been shown to be clearly superior. The aims of this study were to investigate the long-term recurrence rate of a variety of surgical approaches, their associated morbidities and the types of reoperation used to treat recurrence.
METHODS: A retrospective analysis was performed of all cases of rectal prolapse surgery within one colorectal surgical unit between January 2000 and June 2017. Abdominal approaches consisted of rectopexy (RP) and resection rectopexy (RRP); perineal approaches included perineal rectosigmoidectomy (PR) and Delorme's repair (DR). Complications were graded according to the Clavien-Dindo classification. The median follow-up was 4.5 years (interquartile range 1.5-10.1, maximum 16.5). Statistical analysis was performed using Kaplan-Meier to determine recurrence rates.
RESULTS: A total of 157 patients were included in the study. The numbers for each procedure were: DR (n = 55), RRP (n = 44), RP (n = 38) and PR (n = 20). The majority were females (94%). The perineal group were significantly older than the abdominal group (80 versus 67 years, P = 0.0001). At 5 years, the recurrence rates were 52%, 30%, 5% and 3% for DR, PR, RP and RRP, respectively. Morbidity was highest in PR (20%) followed by RRP (18%), RP (16%) and DR (7%) (n.s.). The overall morbidity rates for perineal group and abdominal group were 10.7% and 17.1%, respectively (n.s.).
CONCLUSION: Abdominal approaches have a significantly lower recurrence rate at 5 years but tend to be associated with higher morbidity.

PMID: 31083789 [PubMed - as supplied by publisher]

Differentiation of epileptic regions from voluntary high-gamma activation via interictal cross-frequency windowed power-power correlation.

J Neurosurg. 2019 May 10;:1-11

Authors: Kogan M, Caldwell DJ, Hakimian S, Weaver KE, Ko AL, Ojemann JG

Abstract
OBJECTIVEElectrocorticography is an indispensable tool in identifying the epileptogenic zone in the presurgical evaluation of many epilepsy patients. Traditional electrocorticographic features (spikes, ictal onset changes, and recently high-frequency oscillations [HFOs]) rely on the presence of transient features that occur within or near epileptogenic cortex. Here the authors report on a novel corticography feature of epileptogenic cortex-covariation of high-gamma and beta frequency band power profiles. Band-limited power was measured from each recording site based on native physiological signal differences without relying on clinical ictal or interictal epileptogenic features. In this preliminary analysis, frequency windowed power correlation appears to be a specific marker of the epileptogenic zone. The authors' overall aim was to validate this observation with the location of the eventual resection and outcome.METHODSThe authors conducted a retrospective analysis of 13 adult patients who had undergone electrocorticography for surgical planning at their center. They quantified the correlation of high-gamma (70-200 Hz) and beta (12-18 Hz) band frequency power per electrode site during a cognitive task. They used a sliding window method to correlate the power of smoothed, Hilbert-transformed high-gamma and beta bands. They then compared positive and negative correlations between power in the high-gamma and beta bands in the setting of a hand versus a tongue motor task as well as within the resting state. Significant positive correlations were compared to surgically resected areas and outcomes based on reviewed records.RESULTSPositive high-gamma and beta correlations appeared to predict the area of eventual resection and, preliminarily, surgical outcome independent of spike detection. In general, patients with the best outcomes had well-localized positive correlations (high-gamma and beta activities) to areas of eventual resection, while those with poorer outcomes displayed more diffuse patterns.CONCLUSIONSData in this study suggest that positive high-gamma and beta correlations independent of any behavioral metric may have clinical applicability in surgical decision-making. Further studies are needed to evaluate the clinical potential of this methodology. Additional work is also needed to relate these results to other methods, such as HFO detection or connectivity with other cortical areas.

PMID: 31075773 [PubMed - as supplied by publisher]

Implementation facilitation to promote emergency department-initiated buprenorphine for opioid use disorder: protocol for a hybrid type III effectiveness-implementation study (Project ED HEALTH).

Implement Sci. 2019 05 07;14(1):48

Authors: D'Onofrio G, Edelman EJ, Hawk KF, Pantalon MV, Chawarski MC, Owens PH, Martel SH, VanVeldhuisen P, Oden N, Murphy SM, Huntley K, O'Connor PG, Fiellin DA

Abstract
BACKGROUND: Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for general medical conditions, their addiction, withdrawal symptoms, or complications of injection drug use, such as soft tissue infections. ED-initiated buprenorphine has been shown to be effective in increasing patient engagement in treatment compared with brief intervention with a facilitated referral or referral alone. However, adoption into practice has lagged behind need. To address this implementation challenge, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice.
METHODS: This protocol describes a study that is being conducted through the National Institute on Drug Abuse's Center for the Clinical Trials Network. A hybrid type III effectiveness-implementation study design is used to evaluate the effectiveness of a standard educational dissemination strategy versus IF on implementation (primary) and effectiveness (secondary) outcomes in four urban, academic EDs. Sites start with a standard 60-min "Grand Rounds" educational intervention describing the prevalence of ED patients with OUD, the evidence for opioid agonist treatment and for innovative interventions with ED-initiated buprenorphine; followed by a 1-year baseline evaluation period. Using a modified stepped wedge design, sites are randomly assigned to the IF intervention which is guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework to assess evidence, context, and facilitation-related factors impacting the adoption of ED-initiated buprenorphine. During the 6 months of IF through the 1-year IF evaluation period, external facilitators work with local stakeholders to tailor and refine a bundle of activities to meet the site's needs. The primary analyses compare the baseline evaluation period to the IF evaluation period (n = 120 patients with untreated OUD enrolled during each period) on (1) rates of provision of ED-initiated buprenorphine by ED providers with referral for ongoing medication (implementation outcome) and (2) rates of patient engagement in addiction treatment on the 30th day after the ED visit (effectiveness outcome). Finally, we will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs.
DISCUSSION: Results will generate novel information regarding the impact of IF as a strategy to promote ED-initiated buprenorphine.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03023930 first posted 1/10/2017, https://clinicaltrials.gov/ct2/show/NCT03023930?term=0069&rank=1.

PMID: 31064390 [PubMed - indexed for MEDLINE]

GPR124 regulates microtubule assembly, mitotic progression, and glioblastoma cell proliferation.

Glia. 2019 08;67(8):1558-1570

Authors: Cherry AE, Vicente JJ, Xu C, Morrison RS, Ong SE, Wordeman L, Stella N

Abstract
GPR124 is involved in embryonic development and remains expressed by select organs. The importance of GPR124 during development suggests that its aberrant expression might participate in tumor growth. Here we show that both increases and decreases in GPR124 expression in glioblastoma cells reduce cell proliferation by differentially altering the duration mitotic progression. Using mass spectrometry-based proteomics, we discovered that GPR124 interacts with ch-TOG, a known regulator of both microtubule (MT)-plus-end assembly and mitotic progression. Accordingly, changes in GPR124 expression and ch-TOG similarly affect MT assembly measured by real-time microscopy in cells. Our study describes a novel molecular interaction involving GPR124 and ch-TOG at the plasma membrane that controls glioblastoma cell proliferation by modifying MT assembly rates and controlling the progression of distinct phases of mitosis.

PMID: 31058365 [PubMed - indexed for MEDLINE]

Best Vascular Access in the Elderly: Time for Innovation?

Blood Purif. 2019;47(1-3):236-239

Authors: Asif A, Bakr MM, Levitt M, Vachharajani T

Abstract
BACKGROUND: Conflicting data continue to surround the optimal dialysis access for the elderly. Many propose that catheters are the best option for this population; others emphasize the creation of an arteriovenous fistula.
SUMMARY: While an arteriovenous access is the best available access, it has a high early failure rate, particularly in the elderly. However, significant differences exist in forearm (men ≥65 years ~70%; women ≥65 years ~80%) versus upper arm (men ≥65 years ~40%; women ≥65 years ~38%) fistula failure rates in the elderly, with upper arm having much lower failure rates. Two percutaneous innovative techniques that successfully establish fistulas at the upper arm using proximal radial/ulnar -artery as the inflow have been recently introduced. These procedures have been successfully performed in the elderly. Importantly, these techniques bypass the open surgical exploration and as such avoid the surgical manipulation of the juxta-anastomotic region (a common cause for the development of juxta-anastomotic stenosis and early fistula failure). Key Message: This article discusses the arteriovenous fistula creation in the elderly, highlights the factors necessary for successful fistula creation, and describes the 2 innovative techniques that can be used to provide a robust platform for successful fistula creation in this population.

PMID: 30517921 [PubMed - indexed for MEDLINE]

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]