UW Neurological Surgery Recent PubMed Publications

The Future of Skull Base Surgery: A View Through Tinted Glasses.

World Neurosurg. 2020 10;142:29-42

Authors: Sekhar LN, Juric-Sekhar G, Qazi Z, Patel A, McGrath LB, Pridgeon J, Kalavakonda N, Hannaford B

Abstract
In the present report, we have broadly outlined the potential advances in the field of skull base surgery, which might occur within the next 20 years based on the many areas of current research in biology and technology. Many of these advances will also be broadly applicable to other areas of neurosurgery. We have grounded our predictions for future developments in an exploration of what patients and surgeons most desire as outcomes for care. We next examined the recent developments in the field and outlined several promising areas of future improvement in skull base surgery, per se, as well as identifying the new hospital support systems needed to accommodate these changes. These include, but are not limited to, advances in imaging, Raman spectroscopy and microscopy, 3-dimensional printing and rapid prototyping, master-slave and semiautonomous robots, artificial intelligence applications in all areas of medicine, telemedicine, and green technologies in hospitals. In addition, we have reviewed the therapeutic approaches using nanotechnology, genetic engineering, antitumor antibodies, and stem cell technologies to repair damage caused by traumatic injuries, tumors, and iatrogenic injuries to the brain and cranial nerves. Additionally, we have discussed the training requirements for future skull base surgeons and stressed the need for adaptability and change. However, the essential requirements for skull base surgeons will remain unchanged, including knowledge, attention to detail, technical skill, innovation, judgment, and compassion. We believe that active involvement in these rapidly evolving technologies will enable us to shape some of the future of our discipline to address the needs of both patients and our profession.

PMID: 32599213 [PubMed - indexed for MEDLINE]

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet. 2020 06;16(6):e1008725

Authors: Ferreira MAR, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, Lu Y, Grosche S, Rüschendorf F, Granell R, Brumpton BM, Fritsche LG, Bhatta L, Gabrielsen ME, Nielsen JB, Zhou W, Hveem K, Langhammer A, Holmen OL, Løset M, Abecasis GR, Willer CJ, Emami NC, Cavazos TB, Witte JS, Szwajda A, 23andMe Research Team, collaborators of the SHARE study, Hinds DA, Hübner N, Weidinger S, Magnusson PK, Jorgenson E, Karlsson R, Paternoster L, Boomsma DI, Almqvist C, Lee YA, Koppelman GH

Abstract
Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

PMID: 32603359 [PubMed - indexed for MEDLINE]

A Phase 2 Study of Allogeneic GM-CSF Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer.

Clin Cancer Res. 2020 Jun 26;:

Authors: Wu AA, Bever KM, Ho WJ, Fertig EJ, Niu N, Zheng L, Parkinson RM, Durham JN, Onners BL, Ferguson A, Wilt C, Ko AH, Wang-Gillam A, Laheru DA, Anders RA, Thompson ED, Sugar EA, Jaffee EM, Le DT

Abstract
PURPOSE: This phase 2 study tested granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.
METHODS: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for 4 doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.
RESULTS: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median overall survival (OS) was 9.38 months (95% CI: 5.0, 12.2) for Arm A and 14.7 months (95% CI: 11.6, 20.0) for Arm B (HR 1.75, p=0.019). Using immune related-response criteria, 2 partial responses (5.7%) were observed in Arm A and 4 (13.8%) in Arm B. GVAX + ipilimumab promoted T cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor.
CONCLUSIONS: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

PMID: 32591464 [PubMed - as supplied by publisher]

Mathematical modeling of PDGF-driven glioma reveals the dynamics of immune cells infiltrating into tumors.

Neoplasia. 2020 Jun 22;22(9):323-332

Authors: Niu B, Zeng X, Phan TA, Szulzewsky F, Holte S, Holland EC, Tian JP

Abstract
BACKGROUND: Tumor-infiltrated immune cells compose a significant component of many cancers. They have been observed to have contradictory impacts on tumors. Although the primary reasons for these observations remain elusive, it is important to understand how immune cells infiltrating into tumors is regulated. Recently our group conducted a series of experimental studies, which showed that muIDH1 gliomas have a significant global reduction of immune cells and suggested that the longer survival time of mice with CIMP gliomas may be due to the IDH mutation and its effect on reducing of the tumor-infiltrated immune cells. However, to comprehend how IDH1 mutants regulate infiltration of immune cells into gliomas and how they affect the aggressiveness of gliomas, it is necessary to integrate our experimental data into a dynamical system to acquire a much deeper understanding of subtle regulation of immune cell infiltration.
METHODS: The method is integration of mathematical modeling and experiments. According to mass conservation laws and assumption that immune cells migrate into the tumor site along a chemotactic gradient field, a mathematical model is formulated. Parameters are estimated from our experiments. Numerical methods are developed to solve the problem. Numerical predictions are compared with experimental results.
RESULTS: Our analysis shows that the net rate of increase of immune cells infiltrated into the tumor is approximately proportional to the 4/5 power of the chemoattractant production rate, and it is an increasing function of time while the percentage of immune cells infiltrated into the tumor is a decreasing function of time. Our model predicts that wtIDH1 mice will survive longer if the immune cells are blocked by reducing chemotactic coefficient. For more aggressive gliomas, our model shows that there is little difference in their survivals between wtIDH1 and muIDH1 tumors, and the percentage of immune cells infiltrated into the tumor is much lower. These predictions are verified by our experimental results. In addition, wtIDH1 and muIDH1 can be quantitatively distinguished by their chemoattractant production rates, and the chemotactic coefficient determines possibilities of immune cells migration along chemoattractant gradient fields.
CONCLUSIONS: The chemoattractant gradient field produced by tumor cells may facilitate immune cells migration to the tumor cite. The chemoattractant production rate may be utilized to classify wtIDH1 and muIDH1 tumors. The dynamics of immune cells infiltrating into tumors is largely determined by tumor cell chemoattractant production rate and chemotactic coefficient.

PMID: 32585427 [PubMed - as supplied by publisher]

Insights on cross-species transmission of SARS-CoV-2 from structural modeling.

bioRxiv. 2020 Jun 05;:

Authors: Rodrigues JP, Barrera-Vilarmau S, Teixeira JM, Seckel E, Kastritis P, Levitt M

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 6 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

PMID: 32577636 [PubMed]

Anti-NMDAR-Positive Small-Cell Lung Cancer Paraneoplastic Limbic Encephalitis: A Case Report and Literature Review.

Case Rep Neurol Med. 2020;2020:5269352

Authors: Sohal R, Adams SH, Phogat V, Harish A, Lopez CYD, Williams MPA, Khurana KK, Abuzuaiter B, Jagroop N, Narapureddy B

Abstract
Introduction: Paraneoplastic limbic encephalitis (PLE) is a rare disease that presents as rapid onset dementia characterized by short-term memory loss (STM), anxiety, and behavioral changes. Anti-NMDAR antibodies are unfrequently reported in PLE associated with small-cell lung cancer (SCLC). Given that PLE can precede the diagnosis of cancer, it is very important that once infectious, metabolic, nutritional, or structural disorders associated with short-term memory loss are ruled out that vigorous effort must be made to rule out underlying malignancy.
Case: We report a rare case of PLE as the presenting symptom of SCLC. A 72-year-old male with history of COPD was brought to the ED by his wife after he was found to have short-term memory loss, including forgetfulness of his wedding anniversary the day before, and anxiety. Neurological exam showed impaired short-term recall on MOCA. CT head showed no evidence of infarct. Lumbar puncture was performed which showed lymphocytic pleocytosis, a nonspecific inflammatory change. CSF panel was negative for HSV, Neisseria, Hemophilus, E. coli, and HIV. Initial EEG was unremarkable, though a repeat EEG showed mild slowing of the posterior dominant rhythm consistent with mild encephalopathy. MRI showed equivocal increased FLAIR on T2-weighted images in the bilateral temporal lobes, left greater than right. CTA thorax showed bulky mediastinal and right hilar LAD. FNA of the R4 lymph node revealed SCLC. The NM bone scan showed no osteoblastic lesions. While the serum autoantibody panel was positive for anti-NMDAR, the CSF autoantibody panel returned entirely negative. Chemotherapy with etoposide and cisplatin was started on Day 4 of admission. The patient's neurological symptoms showed improvement following chemotherapy.
Conclusion: This case highlights the importance of recognizing short-term memory loss as a feature of PLE.

PMID: 32566334 [PubMed]

Commentary: Stereotactic Radiosurgery for Intracranial Noncavernous Sinus Benign Meningioma: International Stereotactic Radiosurgery Society Systematic Review, Meta-Analysis and Practice Guideline.

Neurosurgery. 2020 10 15;87(5):E537-E538

Authors: Song AJ, Shi W, Ellenbogen RG, Venur VA, Lo SS

PMID: 32570276 [PubMed - indexed for MEDLINE]

Moyamoya disease and moyamoya syndrome in Ireland: patient demographics, mode of presentation and outcomes of EC-IC bypass surgery.

Ir J Med Sci. 2020 Jun 19;:

Authors: Doherty RJ, Caird J, Crimmins D, Kelly P, Murphy S, McGuigan C, Tubridy N, King MD, Lynch B, Webb D, O'Neill D, McCabe DJH, Boers P, O'Regan M, Moroney J, Williams DJ, Cronin S, Javadpour M

Abstract
BACKGROUND: There are no previously published reports regarding the epidemiology and characteristics of moyamoya disease or syndrome in Ireland.
AIMS: To examine patient demographics, mode of presentation and the outcomes of extracranial-intracranial bypass surgery in the treatment of moyamoya disease and syndrome in Ireland.
METHODS: All patients with moyamoya disease and syndrome referred to the National Neurosurgical Centre during January 2012-January 2019 were identified through a prospective database. Demographics, clinical presentation, radiological findings, surgical procedures, postoperative complications and any strokes during follow-up were recorded.
RESULTS: Twenty-one patients were identified. Sixteen underwent surgery. Median age at diagnosis was 19 years. Fifteen were female. Mode of presentation was ischaemic stroke in nine, haemodynamic TIAs in eight, haemorrhage in three and incidental in one. Sixteen patients had Moyamoya disease, whereas five patients had moyamoya syndrome. Surgery was performed on 19 hemispheres in 16 patients. The surgical procedures consisted of ten direct (STA-MCA) bypasses, five indirect bypasses and four multiple burr holes. Postoperative complications included ischaemic stroke in one patient and subdural haematoma in one patient. The median follow-up period in the surgical group was 52 months; there was one new stroke during this period. Two patients required further revascularisation following recurrent TIAs. One patient died during follow-up secondary to tumour progression associated with neurofibromatosis type 1.
CONCLUSIONS: Moyamoya is rare but occurs in Caucasians in Ireland. It most commonly presents with ischaemic symptoms. Surgical intervention in the form of direct and indirect bypass is an effective treatment in the majority of cases.

PMID: 32562218 [PubMed - as supplied by publisher]

Impact of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features on Revised Bethesda System Malignancy Rates at a Single Institution.

J Surg Res. 2020 11;255:152-157

Authors: Linhares SM, Whitfield BW, Lee AF, Gordillo D, Picado O, Jeraq M, Farrá JC, Lew JI

Abstract
BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) standardizes thyroid cytopathology reporting in six tier diagnostic categories. In recent years, noninvasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study examines the impact of NIFTP on the BSRTC risk of malignancy (ROM).
METHODS: This was a retrospective review of prospectively collected data from 565 patients who underwent fine needle aspiration and thyroidectomy at a single institution. ROM for each Bethesda category was analyzed and calculated with NIFTP classified as a malignant and nonmalignant lesion. Absolute and relative differences between ROM were compared.
RESULTS: Of 565 patients, 19 were Bethesda I, 159 were Bethesda II, 178 were Bethesda III, 46 were Bethesda IV, 42 were Bethesda V, and 121 were Bethesda VI. ROM differences with NIFTP classified as malignant versus nonmalignant for each class were as follows: Bethesda I, no change; Bethesda II, 18%-14%; Bethesda III, 55%-48%; Bethesda IV, 50%-35%; Bethesda V, 93%-91%; and Bethesda VI, 99%-98%. Absolute ROM differences for each category were as follows: Bethesda I, 0%; Bethesda II, 4%; Bethesda III, 7%; Bethesda IV, 15%; Bethesda V, 2%; and Bethesda VI, 1%.
CONCLUSIONS: A decreasing trend in absolute and relative ROM was seen in Bethesda II, III, and IV categories; however, exclusion of NIFTP as a malignant lesion did not significantly alter the ROM of BSRTC categories. Surgeons should assess their respective institution's experiences with NIFTP and the BSRTC.

PMID: 32563006 [PubMed - indexed for MEDLINE]

Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction.

Sci Rep. 2020 06 17;10(1):9766

Authors: Nzou G, Wicks RT, VanOstrand NR, Mekky GA, Seale SA, El-Taibany A, Wicks EE, Nechtman CM, Marrotte EJ, Makani VS, Murphy SV, Seeds MC, Jackson JD, Atala AJ

Abstract
The blood-brain barrier (BBB) is a dynamic component of the brain-vascular interface that maintains brain homeostasis and regulates solute permeability into brain tissue. The expression of tight junction proteins between adjacent endothelial cells and the presence of efflux proteins prevents entry of foreign substances into the brain parenchyma. BBB dysfunction, however, is evident in many neurological disorders including ischemic stroke, trauma, and chronic neurodegenerative diseases. Currently, major contributors to BBB dysfunction are not well understood. Here, we employed a multicellular 3D neurovascular unit organoid containing human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons to model the effects of hypoxia and neuroinflammation on BBB function. Organoids were cultured in hypoxic chamber with 0.1% O2 for 24 hours. Organoids cultured under this hypoxic condition showed increased permeability, pro-inflammatory cytokine production, and increased oxidative stress. The anti-inflammatory agents, secoisolariciresinol diglucoside and 2-arachidonoyl glycerol, demonstrated protection by reducing inflammatory cytokine levels in the organoids under hypoxic conditions. Through the assessment of a free radical scavenger and an anti-inflammatory endocannabinoid, we hereby report the utility of the model in drug development for drug candidates that may reduce the effects of ROS and inflammation under disease conditions. This 3D organoid model recapitulates characteristics of BBB dysfunction under hypoxic physiological conditions and when exposed to exogenous neuroinflammatory mediators and hence may have potential in disease modeling and therapeutic development.

PMID: 32555384 [PubMed - indexed for MEDLINE]

A retrospective descriptive study of cranioplasty failure rates and contributing factors in novel 3D printed calcium phosphate implants compared to traditional materials.

3D Print Med. 2020 Jun 17;6(1):14

Authors: Koller M, Rafter D, Shok G, Murphy S, Kiaei S, Samadani U

Abstract
BACKGROUND: Failure rates with cranioplasty procedures have driven efforts to improve graft material and reduce reoperation. One promising allograft source is a 3D-printed titanium mesh with calcium phosphate filler. This study evaluated failure rates and pertinent characteristics of these novel 3D-grafts compared to traditional materials.
METHODS: Sixty patients were retrospectively identified who underwent a cranioplasty between January 2015-December 2017. Specific data points related to graft failure were collected for all surgical admissions, from the primary injury to their most recent. These included, but were not limited to, initial physical exam findings, vitals, comorbid conditions, surgery length, estimated blood loss, incision type, and need for revision. Failure rates of 3D-printed allografts were compared to traditional grafts.
RESULTS: A total of 60 subjects were identified who underwent 71 unique cranioplasty procedures (3D = 13, Synthetic = 12, Autologous = 46). There were 14 total failures, demonstrating a 19.7% overall failure rate. Specifically, 15.4% (n = 2) of 3D, 19.6% (n = 9) of autologous, and 25.0% (n = 3) of synthetic grafts required revision. Patients receiving 3D-grafts had the shortest overall mean surgery times (200.8 ± 54.3 min) and lowest infection rates (7.7%) compared to autologous (210.5 ± 47.9 min | 25.0%) and synthetic models (217.6 ± 77.3 min | 8.7%), though significance was unable to be determined. Tobacco use and trap-door incisions were associated with increased failure rates relative to straight or curved incisions in autologous grafts. Cranioplasties performed less than 3 months after craniectomy appeared to fail more often than those performed at least three months after craniectomy, for the synthetic group.
CONCLUSION: We concluded that 3D-printed cranioplasty grafts may lead to lower failure rates and shorter surgery times compared to traditional cranioplasty materials in our limited population. 3D-implants hold promise for cranial reconstruction after TBI.

PMID: 32556704 [PubMed]

Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.

J Neurooncol. 2020 Jun 16;:

Authors: Crotty EE, Leary SES, Geyer JR, Olson JM, Millard NE, Sato AA, Ermoian RP, Cole BL, Lockwood CM, Paulson VA, Browd SR, Ellenbogen RG, Hauptman JS, Lee A, Ojemann JG, Vitanza NA

Abstract
INTRODUCTION: Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation.
METHODS: We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.
RESULTS: Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG.
CONCLUSION: Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

PMID: 32556862 [PubMed - as supplied by publisher]

Management of benign prostatic hyperplasia in the 21st century: temporal trends in Australian population-based data.

BJU Int. 2020 09;126 Suppl 1:18-26

Authors: Morton A, Williams M, Perera M, Teloken PE, Donato P, Ranasinghe S, Chung E, Bolton D, Yaxley J, Roberts MJ

Abstract
OBJECTIVE: To examine national trends in the medical and surgical treatment of benign prostatic hyperplasia (BPH) using Australian Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) population data from 2000 to 2018.
PATIENTS AND METHODS: Annual data was extracted from the MBS, PBS and Australian Institute of Health and Welfare databases for the years 2000-2018. Population-adjusted rates of BPH procedures and medical therapies were calculated and compared in relation to age. Cost analysis was performed to estimate financial burden due to BPH.
RESULTS: Overall national hospital admissions due to BPH declined between 2000 and 2018, despite an increased proportion of admissions due to private procedures (42% vs 77%). Longitudinal trends in the medical management of BPH showed an increased prescription rate of dutasteride/tamsulosin combined therapy (111 vs 7649 per 100 000 men) and dutasteride monotherapy (149 vs 336 per 100 000 men) since their introduction to the PBS in 2011. Trends in BPH surgery showed an overall progressive increase in rate of total procedures between 2000 and 2018 (92 vs 133 per 100 000 men). Transurethral resection of the prostate (TURP) remained the most commonly performed surgical procedure, despite reduced utilisation since 2009 (118 vs 89 per 100 000 men), offset by a higher uptake of photoselective vaporisation of prostate, holmium:YAG laser enucleation of prostate, and later likely due to minimally invasive surgical therapies including prostatic urethral lift and ablative technologies (including Rezūm™). Financial burden due to BPH surgery has remained steady since 2009, whilst the burden due to medical therapy has risen sharply.
CONCLUSION: Despite reduced national BPH-related hospitalisations, overall treatment for BPH has increased due to medical therapy and surgical alternatives to TURP. Further exploration into motivators for particular therapies and effect of medical therapy on BPH progression in clinical practice outside of clinical trials is warranted.

PMID: 32558340 [PubMed - indexed for MEDLINE]

Regional Dichotomy in Enteric Mucosal Immune Responses to a Persistent Mycobacterium avium ssp. paratuberculosis Infection.

Front Immunol. 2020;11:1020

Authors: Facciuolo A, Lee AH, Gonzalez Cano P, Townsend HGG, Falsafi R, Gerdts V, Potter A, Napper S, Hancock REW, Mutharia LM, Griebel PJ

Abstract
Chronic enteric Mycobacterium avium ssp. paratuberculosis (MAP) infections are endemic in ruminants globally resulting in significant production losses. The mucosal immune responses occurring at the site of infection, specifically in Peyer's patches (PP), are not well-understood. The ruminant small intestine possesses two functionally distinct PPs. Discrete PPs function as mucosal immune induction sites and a single continuous PP, in the terminal small intestine, functions as a primary lymphoid tissue for B cell repertoire diversification. We investigated whether MAP infection of discrete vs. continuous PPs resulted in the induction of significantly different pathogen-specific immune responses and persistence of MAP infection. Surgically isolated intestinal segments in neonatal calves were used to target MAP infection to individual PPs. At 12 months post-infection, MAP persisted in continuous PP (n = 4), but was significantly reduced (p = 0.046) in discrete PP (n = 5). RNA-seq analysis revealed control of MAP infection in discrete PP was associated with extensive transcriptomic changes (1,707 differentially expressed genes) but MAP persistent in continuous PP elicited few host responses (4 differentially expressed genes). Cytokine gene expression in tissue and MAP-specific recall responses by mucosal immune cells isolated from PP, lamina propria and mesenteric lymph node revealed interleukin (IL)22 and IL27 as unique correlates of protection associated with decreased MAP infection in discrete PP. This study provides the first description of mucosal immune responses occurring in bovine discrete jejunal PPs and reveals that a significant reduction in MAP infection is associated with specific cytokine responses. Conversely, MAP infection persists in the continuous ileal PP with minimal perturbation of host immune responses. These data reveal a marked dichotomy in host-MAP interactions within the two functionally distinct PPs of the small intestine and identifies mucosal immune responses associated with the control of a mycobacterial infection in the natural host.

PMID: 32547548 [PubMed - in process]

Analysis of Normal High-Frequency Intracranial Pressure Values and Treatment Threshold in Neurocritical Care Patients: Insights into Normal Values and a Potential Treatment Threshold.

JAMA Neurol. 2020 Jun 15;:

Authors: Hawryluk GWJ, Nielson JL, Huie JR, Zimmermann L, Saigal R, Ding Q, Hirschi R, Zeiler FA, Ferguson A, Manley G

Abstract
Importance: Intracranial pressure (ICP) elevation is a compartment syndrome that impairs blood flow to the brain. Despite the importance of ICP values in neurocritical care, normal ICP values and the precise ICP threshold at which treatment should be initiated remain uncertain.
Objective: To refine our understanding of normal ICP values and determine the ICP threshold most strongly associated with outcome.
Design, Setting, and Participants: Prospective observational study (2004-2010), with outcomes determined at hospital discharge. The study included neurocritical care patients from a single level I trauma center, San Francisco General Hospital. Three hundred eighty-three patients had a traumatic brain injury with or without craniectomy; 140 patients had another indication for ICP monitoring. Consecutive patients were studied. Data analyses were completed between March 2015 and December 2019.
Exposures: Five hundred twenty-three ICP-monitored patients.
Main Outcomes and Measures: A computer system prospectively and automatically collected 1-minute physiologic data from patients in the intensive care unit during a 6-year period. Mean ICP was calculated, as was the proportion of ICP values greater than thresholds from 1 to 80 mm Hg in 1-mm Hg increments. The association between these measures and outcome was explored for various epochs up to 30 days from the time of injury. A principal component analysis was used to explore physiologic changes at various ICP thresholds, and elastic net regression was used to identify ICP thresholds most strongly associated with Glasgow Outcome Scale score at discharge.
Results: Of the 523 studied patients, 70.7% of studied patients were men (n = 370) and 72.1% had a traumatic brain injury (n = 377). A total of 4 090 964 1-minute ICP measurements were recorded for the included patients (7.78 years of recordings). Intracranial pressure values of 8 to 9 mm Hg were most commonly recorded and could possibly reflect normal values. The principal component analysis suggested state shifts in the physiome occurred at ICPs greater than 19 mm Hg and 24 mm Hg. Elastic net regression identified an ICP threshold of 19 mm Hg as most robustly associated with outcome when considering all neurocritical care patients, patients with TBI, and patients with TBI who underwent craniectomy. Intracranial pressure values greater than 19 mm Hg were associated with mortality, while lower values were associated with outcome in surviving patients.
Conclusions and Relevance: This study provides insight into what normal ICP values could be. An ICP threshold of 19 mm Hg was robustly associated with outcome in studied patients, although lower ICP values were associated with outcome in surviving patients.

PMID: 32539101 [PubMed - as supplied by publisher]

Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis.

Circulation. 2020 Jun 16;141(24):2031-2034

Authors: Zhang L, Zlotoff DA, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zubiri L, Chen CL, Sullivan RJ, Alvi RM, Rokicki A, Murphy SP, Jones-O'Connor M, Heinzerling LM, Barac A, Forrestal BJ, Yang EH, Gupta D, Kirchberger MC, Shah SP, Rizvi MA, Sahni G, Mandawat A, Mahmoudi M, Ganatra S, Ederhy S, Zatarain-Nicolas E, Groarke JD, Tocchetti CG, Lyon AR, Thavendiranathan P, Cohen JV, Reynolds KL, Fradley MG, Neilan TG

PMID: 32539614 [PubMed - in process]

CBASS Immunity Uses CARF-Related Effectors to Sense 3'-5'- and 2'-5'-Linked Cyclic Oligonucleotide Signals and Protect Bacteria from Phage Infection.

Cell. 2020 07 09;182(1):38-49.e17

Authors: Lowey B, Whiteley AT, Keszei AFA, Morehouse BR, Mathews IT, Antine SP, Cabrera VJ, Kashin D, Niemann P, Jain M, Schwede F, Mekalanos JJ, Shao S, Lee ASY, Kranzusch PJ

Abstract
cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Oligonucleotide recognition occurs through an appended SAVED domain that is an unexpected fusion of two CRISPR-associated Rossman fold (CARF) subunits co-opted from type III CRISPR immunity. Like a lock and key, SAVED effectors exquisitely discriminate 2'-5'- and 3'-5'-linked bacterial cyclic oligonucleotide signals and enable specific recognition of at least 180 potential nucleotide second messenger species. Our results reveal SAVED CARF family proteins as major nucleotide second messenger receptors in CBASS and CRISPR immune defense and extend the importance of linkage specificity beyond mammalian cGAS-STING signaling.

PMID: 32544385 [PubMed - indexed for MEDLINE]

The stress-inducible molecular chaperone GRP78 as potential therapeutic target for coronavirus infection.

J Infect. 2020 09;81(3):452-482

Authors: Ha DP, Van Krieken R, Carlos AJ, Lee AS

PMID: 32535155 [PubMed - indexed for MEDLINE]

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.

Nat Commun. 2020 06 12;11(1):2977

Authors: Pattwell SS, Arora S, Cimino PJ, Ozawa T, Szulzewsky F, Hoellerbauer P, Bonifert T, Hoffstrom BG, Boiani NE, Bolouri H, Correnti CE, Oldrini B, Silber JR, Squatrito M, Paddison PJ, Holland EC

Abstract
Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

PMID: 32532995 [PubMed - indexed for MEDLINE]

Variation in hospital charges in patients with external ventricular drains: comparison between the intensive care and surgical floor settings.

J Neurosurg Pediatr. 2019 04 19;24(1):29-34

Authors: Chu JK, Feroze AH, Collins K, McGrath LB, Young CC, Williams JR, Browd SR

Abstract
OBJECTIVE: Placement of an external ventricular drain (EVD) is a common and potentially life-saving neurosurgical procedure, but the economic aspect of EVD management and the relationship to medical expenditure remain poorly studied. Similarly, interinstitutional practice patterns vary significantly. Whereas some institutions require that patients with EVDs be monitored strictly within the intensive care unit (ICU), other institutions opt primarily for management of EVDs on the surgical floor. Therefore, an ICU burden for patients with EVDs may increase a patient's costs of hospitalization. The objective of the current study was to examine the expense differences between the ICU and the general neurosurgical floor for EVD care.
METHODS: The authors performed a retrospective analysis of data from 2 hospitals within a single, large academic institution-the University of Washington Medical Center (UWMC) and Seattle Children's Hospital (SCH). Hospital charges were evaluated according to patients' location at the time of EVD management: SCH ICU, SCH floor, or UWMC ICU. Daily hospital charges from day of EVD insertion to day of removal were included and screened for days that would best represent baseline expenses for EVD care. Independent-samples Kruskal-Wallis analysis was performed to compare daily charges for the 3 settings.
RESULTS: Data from a total of 261 hospital days for 23 patients were included in the analysis. Ten patients were cared for in the UWMC ICU and 13 in the SCH ICU and/or on the SCH neurosurgical floor. The median values for total daily hospital charges were $19,824.68 (interquartile range [IQR] $12,889.73-$38,494.81) for SCH ICU care, $8,620.88 (IQR $6,416.76-$11,851.36) for SCH floor care, and $10,002.13 (IQR $8,465.16-$12,123.03) for UWMC ICU care. At SCH, it was significantly more expensive to provide EVD care in the ICU than on the floor (p < 0.001), and the daily hospital charges for the UWMC ICU were significantly greater than for the SCH floor (p = 0.023). No adverse clinical event related to the presence of an EVD was identified in any of the settings.
CONCLUSIONS: ICU admission solely for EVD care is costly. If safe EVD care can be provided outside of the ICU, it would represent a potential area for significant cost savings. Identifying appropriate patients for EVD care on the floor is multifactorial and requires vigilance in balancing the expenses associated with ICU utilization and optimal patient care.

PMID: 31003227 [PubMed - indexed for MEDLINE]