UW Neurological Surgery Recent PubMed Publications

Importance of neuropsychological screening in physicians referred for performance concerns.

PLoS One. 2018;13(11):e0207874

Authors: Williams BW, Flanders P, Welindt D, Williams MV

Abstract
INTRODUCTION: The literature suggests that 6-12% of practicing physicians are dyscompetent. Dyscompetence can manifest as failures in direct provision of care, but also issues with interpersonal and communications skills and professionalism. There is a growing literature suggesting the value of neurocognitive screening in physicians with clinical competency issues. The contribution of such screening in physicians with workplace behavioral issues is not as established. The aim of this exploratory study was to examine patterns of performance on a commonly used neuropsychological screening instrument. Performances differences, if present, could have implications for remediation and/or monitoring.
METHODS: Published data on a computerized neurocognitive screening instrument (MicroCog) for normative physician samples, published data on physicians referred for clinical competency issues, and newly collected data on physicians with workplace behavioral issues were analyzed. A two-way analysis of variance (Sample X Index) and post-hoc paired comparisons were conducted. A second analysis was performed employing an aggregated estimate of normative physician performance.
RESULTS: Results revealed a significant main effect for Sample and Index and a significant interaction effect. The second analysis of variance employing the pooled samples (Sample X Index) was conducted. The workplace behavior issues sample differed significantly from each of the samples. The Sample by Index interaction was significant.
DISCUSSION: Significant differences in performance on a neurocognitive screening instrument were found between non-referred physicians and physicians with behavioral or medical/technical competency concerns. Those with workplace behavioral issues performed significantly better than those with medical/technical issues, but significantly worse than non-referred physicians. Using these findings, 2.0% of the normal sample versus 35.1% of the medical/technical sample, and 10.9% of the behavioral sample would fail the screen using typical, conservative cutoffs. Further study of the potential role of neurocognitive factors in physicians referred for behavioral comportment issues is warranted.

PMID: 30475869 [PubMed - in process]

Reconstructing patient-specific cerebral aneurysm vasculature for in vitro investigations and treatment efficacy assessments.

J Clin Neurosci. 2019 Mar;61:153-159

Authors: Chivukula VK, Levitt MR, Clark A, Barbour MC, Sansom K, Johnson L, Kelly CM, Geindreau C, Rolland du Roscoat S, Kim LJ, Aliseda A

Abstract
Perianeurysmal hemodynamics play a vital role in the initiation, growth and rupture of intracranial aneurysms. In vitro investigations of aneurysmal hemodynamics are helpful to visualize and measure blood flow, and aiding surgical planning approaches. Improving in vitro model creation can improve the feasibility and accuracy of hemodynamic investigations and surgical planning, improving clinical value. In this study, in vitro models were created from three-dimensional rotational angiography (3DRA) of six patients harboring intracranial aneurysms using a multi-step process involving 3D printing, index of refraction matching and silicone casting that renders the models transparent for flow visualization. Each model was treated with the same commercially-available, patient-specific, endovascular devices (coils and/or stents). All models were scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the vessel lumen, aneurysmal sac and endovascular devices. Dimensional accuracy was compared by quantifying the differences between the microtomographic reconstructions of the fabricated phantoms and the original 3DRA obtained during patient treatment. True-scale in vitro flow phantoms were successfully created for all six patients. Optical transparency was verified by using an index of refraction matched working fluid that replicated the mechanical behavior of blood. Synchrotron imaging of vessel lumen, aneurysmal sac and endovascular devices was successfully obtained, and dimensional errors were found to be O(100 μm). The creation of dimensionally-accurate, optically-transparent flow phantoms of patient-specific intracranial aneurysms is feasible using 3D printing technology. Such models may enable in vitro investigations of aneurysmal hemodynamics to aid in treatment planning and outcome prediction to devise optimal patient-specific neurointerventional strategies.

PMID: 30470652 [PubMed - indexed for MEDLINE]

Exploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis.

Nat Commun. 2017 04 25;8:15013

Authors: Yeung ATY, Hale C, Lee AH, Gill EE, Bushell W, Parry-Smith D, Goulding D, Pickard D, Roumeliotis T, Choudhary J, Thomson N, Skarnes WC, Dougan G, Hancock REW

Abstract
Chlamydia trachomatis remains a leading cause of bacterial sexually transmitted infections and preventable blindness worldwide. There are, however, limited in vitro models to study the role of host genetics in the response of macrophages to this obligate human pathogen. Here, we describe an approach using macrophages derived from human induced pluripotent stem cells (iPSdMs) to study macrophage-Chlamydia interactions in vitro. We show that iPSdMs support the full infectious life cycle of C. trachomatis in a manner that mimics the infection of human blood-derived macrophages. Transcriptomic and proteomic profiling of the macrophage response to chlamydial infection highlighted the role of the type I interferon and interleukin 10-mediated responses. Using CRISPR/Cas9 technology, we generated biallelic knockout mutations in host genes encoding IRF5 and IL-10RA in iPSCs, and confirmed their roles in limiting chlamydial infection in macrophages. This model can potentially be extended to other pathogens and tissue systems to advance our understanding of host-pathogen interactions and the role of human genetics in influencing the outcome of infections.

PMID: 28440293 [PubMed - indexed for MEDLINE]

Diagnostic challenges of prolonged post-treatment clearance of Plasmodium nucleic acids in a pre-transplant autosplenectomized patient with sickle cell disease.

Malar J. 2018 01 10;17(1):23

Authors: Luethy PM, Murphy SC, Seilie AM, Xie YL, Lau CY, Tisdale JF, Hsieh MM, Reinhardt JL, Lau AF, Fahle GA

Abstract
BACKGROUND: Autosplenectomy, as a result of sickle cell disease, is an important risk factor for severe malaria. While molecular methods are helpful in providing rapid and accurate infection detection and species identification, the effect of hyposplenism on result interpretation during the course of infection should be carefully considered.
CASE PRESENTATION: A 32-year old autosplenectomized Nigerian male with severe sickle cell disease was referred to the National Institutes of Health for allogenic hematopoietic stem cell transplant. Despite testing negative for malaria by both smear and PCR 2 weeks after arrival in the USA, the patient developed fever and diffuse bilateral lower rib cage and upper abdominal pain 2 weeks later and subsequently tested positive for Plasmodium falciparum. Parasitaemia was tracked over time by microscopy and nucleic acid tests to evaluate the therapeutic response in the setting of hyposplenism. The patient showed prompt resolution of patent infection by microscopy but remained positive by molecular methods for > 30 days after treatment initiation.
CONCLUSION: While molecular testing can provide sensitive Plasmodium nucleic acid detection, the persistence of Plasmodium nucleic acids following adequate treatment in functionally asplenic patients can lead to a diagnostic dilemma. In such patients, clinical response and peripheral blood smears should guide patient management following treatment. Nonetheless, in pre-transplant patients at high-risk for pre-existing Plasmodium infections, highly sensitive molecular assays can be useful to rule out infection prior to transplantation.

PMID: 29321025 [PubMed - indexed for MEDLINE]

Cost of pharmacotherapy for opioid use disorders following inpatient detoxification.

Am J Manag Care. 2018 11;24(11):526-531

Authors: McCollister KE, Leff JA, Yang X, Lee JD, Nunes EV, Novo P, Rotrosen J, Schackman BR, Murphy SM

Abstract
OBJECTIVES: To estimate the costs of providing extended-release injectable naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) following inpatient detoxification using data derived from a multisite randomized controlled trial at 8 US community-based treatment programs.
STUDY DESIGN: Cost data were collected for 3 intervention phases: program start-up, inpatient detoxification, and up to 24 weeks of medication induction and management visits (post detoxification). Cost analyses were from the healthcare sector perspective (2015 US$); patient costs are also reported.
METHODS: We conducted site visits, administered a cost survey to treatment programs, and analyzed study data on medication and services utilization. Nationally representative sources were used to estimate unit costs. Uncertainty was evaluated in sensitivity analyses.
RESULTS: Mean start-up costs were $1071 per program for XR-NTX and $828 per program for BUP-NX. Mean costs per participant were $5416 for XR-NTX (57% detoxification, 37% medication, 3% provider, 3% patient) and $4148 for BUP-NX (64% detoxification, 12% medication, 10% provider, 14% patient). Total cost per participant ranged by site from $2979 to $8963 for XR-NTX and from $2521 to $6486 for BUP-NX.
CONCLUSIONS: For treatment providers, offering XR-NTX and/or BUP-NX as part of existing detoxification treatment modalities generates modest costs in addition to the costs of detoxification, which vary substantially among the 8 sites. From the patient's perspective, the costs associated with medication management visits may be a barrier for some individuals considering these treatments.

PMID: 30452209 [PubMed - indexed for MEDLINE]

Is Schizophrenia a Risk Factor for Breast Cancer?-Evidence From Genetic Data.

Schizophr Bull. 2019 10 24;45(6):1251-1256

Authors: Byrne EM, Ferreira MAR, Xue A, Lindström S, Jiang X, Yang J, Easton DF, Wray NR, Chenevix-Trench G

Abstract
Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

PMID: 30452727 [PubMed - indexed for MEDLINE]

A New Method for the Anterior Mitral Leaflet Segmentation in Echocardiography Videos using the Virtual M-mode Space.

Conf Proc IEEE Eng Med Biol Soc. 2018 07;2018:3120-3123

Authors: Sultanl MS, Martins N, Costa E, Veiga D, Ferreira MJ, Mattos S, Coimbra MT

Abstract
Rheumatic heart disease is responsible for the heart valve damage, caused by repeated episodes of rheumatic fever. The disease commonly inflames and scars the mitral valve of the heart, resulting in thicker, less mobile leaflets, with associated decrease in cardiac efficiency. It is important to measure and quantity the early manifestations of this disease, including variations of the thickness, shape and mobility of the leaflets. These manifestations are visible in an echocardiographic screening process. The first step towards the defined objective is to segment the anterior mitral leaflet throughout the cardiac cycle, enabling the future automatic quantification of mentioned clinical parameters. In this work, a new algorithm for the segmentation of the whole region of the anterior mitral leaflet in the virtual M-mode space is proposed. The algorithm requires a single initialization point on the posterior wall of the aorta, in the first frame of the video. A junction point is then computed, showing the location where the two leaflets connect. This junction point helps to automatically redefine the range of virtual M-mode images required to completely segment the region of the anterior mitral leaflet. The segmented anterior mitral leaflet region in the virtual M-mode space is transferred back to regular image space and its shape refined using localized active contours. Results suggest the suitability of the proposed algorithm for the segmentation of anterior mitral leaflet with a median Dice Similarity Coefficient of 0.63, and with median precision and recall of 58% and 73% respectively.

PMID: 30441055 [PubMed - indexed for MEDLINE]

Fully Automatic Finger Extensor Tendon Segmentation in Ultrasound Images of the Metacarpophalangeal Joint.

Conf Proc IEEE Eng Med Biol Soc. 2018 07;2018:3406-3409

Authors: Martins N, Sultan MS, Veiga D, Ferreira M, Coimbra M

Abstract
In this work a fully automatic system to identify the extensor tendon on ultrasound images of the metacarpophalangeal joint is proposed. These images are used to diagnose rheumatic diseases which are one of the main causes of impairment and pain in developed countries. The early diagnosis of these conditions is crucial to a proper treatment and follow-up and so, a system such as the one proposed here, could be useful to automatically extract relevant information from the resulting images. This work is an extension of a previous published work which uses manual annotations of the skin line, metacarpus and phalange to guide the extensor tendon segmentation. By introducing automatic segmentations of all structures, we expect to create a fully automatic system, which is more interesting to the possible end-users. Results show that, despite an expected loss in the performance, it is still possible to correctly identify the extensor tendon with a Confidence of 88% considering a maximum allowed Modified Hausdorff Distance of 0.5mm.

PMID: 30441119 [PubMed - indexed for MEDLINE]

Extracting Thickness Profiles of Anterior Mitral Leaflets in Echocardiography Videos.

Conf Proc IEEE Eng Med Biol Soc. 2018 07;2018:3582-3585

Authors: Pires L, Sultan MS, Martins N, Costa E, Veiga D, Ferreira MJ, Mattos S, Coimbra MT

Abstract
Rheumatic heart disease is the serious consequence of repeated episodes of acute rheumatic fever. It is the major cause of heart valve damage resulting in morbidity and mortality. Its early detection is considered vital to control the disease's progression. The key manifestations that are visible in the early stages of this disease are changes in the thickness, shape and mobility of the mitral valve leaflets. Echocardiography based screening is sensitive enough to identify these changes in early stages of the disease. In this work, an automatic approach is proposed to measure, quantify and analyze the thickness of the anterior mitral leaflet, in an echocardiographic video. The shape of the anterior mitral leaflet is simplified via morphological skeletonization and spline modelling to get the central line of the leaflet. To analyze the overall thickness from the tip to its base, the anterior mitral leaflet is divided into four quartiles. In ach quartile the thickness is measured as the length of the line segment resulting from the intersection of the contour with the normal direction of the central point of each quartile. Finally, the thickness is analyzed by measuring the variance per quartile, divided by leaflet position (open, straight and closed). The comparison between the normal and pathological leaflets are also presented, exhibiting statistical significant differences in all quartiles, especially near the tip of the leaflet.

PMID: 30441152 [PubMed - indexed for MEDLINE]

A machine-learning approach to volitional control of a closed-loop deep brain stimulation system.

J Neural Eng. 2019 02;16(1):016004

Authors: Houston B, Thompson M, Ko A, Chizeck H

Abstract
OBJECTIVE: Deep brain stimulation (DBS) is a well-established treatment for essential tremor, but may not be an optimal therapy, as it is always on, regardless of symptoms. A closed-loop (CL) DBS, which uses a biosignal to determine when stimulation should be given, may be better. Cortical activity is a promising biosignal for use in a closed-loop system because it contains features that are correlated with pathological and normal movements. However, neural signals are different across individuals, making it difficult to create a 'one size fits all' closed-loop system.
APPROACH: We used machine learning to create a patient-specific, CL DBS system. In this system, binary classifiers are used to extract patient-specific features from cortical signals and determine when volitional, tremor-evoking movement is occurring to alter stimulation voltage in real time.
MAIN RESULTS: This system is able to deliver stimulation up to 87%-100% of the time that subjects are moving. Additionally, we show that the therapeutic effect of the system is at least as good as that of current, continuous-stimulation paradigms.
SIGNIFICANCE: These findings demonstrate the promise of CL DBS therapy and highlight the importance of using subject-specific models in these systems.

PMID: 30444218 [PubMed - indexed for MEDLINE]

The Impact of Organizational Culture on Leadership Burnout.

Front Health Serv Manage. 2018;35(2):34-37

Authors: Williams MD

PMID: 30433903 [PubMed - indexed for MEDLINE]

The Endoplasmic Reticulum Chaperone GRP78/BiP Modulates Prion Propagation in vitro and in vivo.

Sci Rep. 2017 03 23;7:44723

Authors: Park KW, Eun Kim G, Morales R, Moda F, Moreno-Gonzalez I, Concha-Marambio L, Lee AS, Hetz C, Soto C

Abstract
Prion diseases are fatal neurodegenerative disorders affecting several mammalian species, characterized by the accumulation of the misfolded form of the prion protein, which is followed by the induction of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis due to an enhancement of the cellular folding capacity. Here, we studied the role of GRP78 in prion diseases using several in vivo and in vitro approaches. Our results show that a reduction in the expression of this molecular chaperone accelerates prion pathogenesis in vivo. In addition, we observed that prion replication in cell culture was inversely related to the levels of expression of GRP78 and that both proteins interact in the cellular context. Finally, incubation of PrPSc with recombinant GRP78 led to the dose-dependent reduction of protease-resistant PrPSc in vitro. Our results uncover a novel role of GRP78 in reducing prion pathogenesis, suggesting that modulating its levels/activity may offer a novel opportunity for designing therapeutic approaches for these diseases. These findings may also have implications for other diseases involving the accumulation of misfolded proteins.

PMID: 28333162 [PubMed - indexed for MEDLINE]

Hepatitis B Virus Therapeutic Agent ARB-1740 Has Inhibitory Effect on Hepatitis Delta Virus in a New Dually-Infected Humanized Mouse Model.

ACS Infect Dis. 2019 05 10;5(5):738-749

Authors: Ye X, Tateno C, Thi EP, Kakuni M, Snead NM, Ishida Y, Barnard TR, Sofia MJ, Shimada T, Lee ACH

Abstract
Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts, and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually infected humanized mice. Treatment with ARB-1740, a clinical stage HBV-targeting siRNA agent delivered using lipid nanoparticle (LNP) technology, effectively reduced HBV viremia by 2.3 log10 and serum HBsAg by 2.6 log10, leading to 1.6 log10 reduction of HDV viremia. In contrast, HDV-targeting siRNA inhibited HDV in both blood and liver compartments without affecting HBV and PEGylated interferon-alpha reduced HBV viremia by 2.0 log10 but had no effect on HDV viremia under these study conditions. These results illustrate the inhibitory effects of siRNAs against these two viral infections and suggest that ARB-1740 may be of therapeutic benefit for hepatitis delta patients, a subpopulation with high unmet medical need.

PMID: 30408957 [PubMed - indexed for MEDLINE]

Synthesis and Evaluation of Baylis-Hillman Reaction Derived Imidazole and Triazole Cinnamates as Antifungal Agents.

Int J Med Chem. 2018;2018:5758076

Authors: Nelson GL, Williams MJ, Jonnalagadda S, Alam MA, Mereddy G, Johnson JL, Jonnalagadda SK

Abstract
Allylic acetates derived from Baylis-Hillman reaction undergo efficient nucleophilic isomerization with imidazoles and triazoles to provide imidazolylmethyl and triazolylmethyl cinnamates stereoselectively. Antifungal evaluation of these derivatives against Cryptococcus neoformans exhibits good minimum inhibitory concentration values. These compounds exhibit low toxicity in proliferating MCF-7 breast cancer cell line. Structure activity relationship studies indicate that halogenated aromatic derivatives provide better antifungal activity.

PMID: 30410798 [PubMed]

Comparative functional genomic screens of three yeast deletion collections reveal unexpected effects of genotype in response to diverse stress.

Open Biol. 2017 06;7(6):

Authors: Acton E, Lee AH, Zhao PJ, Flibotte S, Neira M, Sinha S, Chiang J, Flaherty P, Nislow C, Giaever G

Abstract
The Yeast Knockout (YKO) collection has provided a wealth of functional annotations from genome-wide screens. An unintended consequence is that 76% of gene annotations derive from one genotype. The nutritional auxotrophies in the YKO, in particular, have phenotypic consequences. To address this issue, 'prototrophic' versions of the YKO collection have been constructed, either by introducing a plasmid carrying wild-type copies of the auxotrophic markers (Plasmid-Borne, PBprot) or by backcrossing (Backcrossed, BCprot) to a wild-type strain. To systematically assess the impact of the auxotrophies, genome-wide fitness profiles of prototrophic and auxotrophic collections were compared across diverse drug and environmental conditions in 250 experiments. Our quantitative profiles uncovered broad impacts of genotype on phenotype for three deletion collections, and revealed genotypic and strain-construction-specific phenotypes. The PBprot collection exhibited fitness defects associated with plasmid maintenance, while BCprot fitness profiles were compromised due to strain loss from nutrient selection steps during strain construction. The repaired prototrophic versions of the YKO collection did not restore wild-type behaviour nor did they clarify gaps in gene annotation resulting from the auxotrophic background. To remove marker bias and expand the experimental scope of deletion libraries, construction of a bona fide prototrophic collection from a wild-type strain will be required.

PMID: 28592509 [PubMed - indexed for MEDLINE]

Simultaneous Quantification of Plasmodium Antigens and Host Factor C-Reactive Protein in Asymptomatic Individuals with Confirmed Malaria by Use of a Novel Multiplex Immunoassay.

J Clin Microbiol. 2019 01;57(1):

Authors: Jang IK, Tyler A, Lyman C, Kahn M, Kalnoky M, Rek JC, Arinaitwe E, Adrama H, Murphy M, Imwong M, Ling CL, Proux S, Haohankhunnatham W, Rist M, Seilie AM, Hanron A, Daza G, Chang M, Das S, Barney R, Rashid A, Landier J, Boyle DS, Murphy SC, McCarthy JS, Nosten F, Greenhouse B, Domingo GJ

Abstract
Malaria rapid diagnostic tests (RDTs) primarily detect Plasmodium falciparum antigen histidine-rich protein 2 (HRP2) and the malaria-conserved antigen lactate dehydrogenase (LDH) for P. vivax and other malaria species. The performance of RDTs and their utility is dependent on circulating antigen concentration distributions in infected individuals in a population in which malaria is endemic and on the limit of detection of the RDT for the antigens. A multiplexed immunoassay for the quantification of HRP2, P. vivax LDH, and all-malaria LDH (pan LDH) was developed to accurately measure circulating antigen concentration and antigen distribution in a population with endemic malaria. The assay also measures C-reactive protein (CRP) levels as an indicator of inflammation. Validation was conducted with clinical specimens from 397 asymptomatic donors from Myanmar and Uganda, confirmed by PCR for infection, and from participants in induced blood-stage malaria challenge studies. The assay lower limits of detection for HRP2, pan LDH, P. vivax LDH, and CRP were 0.2 pg/ml, 9.3 pg/ml, 1.5 pg/ml, and 26.6 ng/ml, respectively. At thresholds for HRP2, pan LDH, and P. vivax LDH of 2.3 pg/ml, 47.8 pg/ml, and 75.1 pg/ml, respectively, and a specificity ≥98.5%, the sensitivities for ultrasensitive PCR-confirmed infections were 93.4%, 84.9%, and 48.9%, respectively. Plasmodium LDH (pLDH) concentration, in contrast to that of HRP2, correlated closely with parasite density. CRP levels were moderately higher in P. falciparum infections with confirmed antigenemia versus those in clinical specimens with no antigen. The 4-plex array is a sensitive tool for quantifying diagnostic antigens in malaria infections and supporting the evaluation of new ultrasensitive RDTs.

PMID: 30404944 [PubMed - indexed for MEDLINE]

Microsurgical Clipping of a Ruptured Basilar Apex Aneurysm: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Nov 08;:

Authors: Cheng CY, Qazi Z, Hallam DK, Ghodke BV, Sekhar LN

Abstract
A 59-yr-old woman presented with a sudden onset of headache with neck pain and stiffness, Hunt and Hess grade 2. Brain computed tomography (CT) showed subarachnoid hemorrhage, Fisher Grade 2. Intra-arterial digital subtraction angiography (IADSA) showed a basilar artery apex aneurysm, dome size 9 mm and neck 3 mm, leaning towards the right, and a dominant right artery of Percheron. Endovascular treatment and microsurgical clipping were both explained to the patient, but she decided to undergo microsurgery due to the durability of treatment.She underwent a right frontotemporal craniotomy and orbital osteotomy. We performed optic nerve decompression and intradural anterior clinoidectomy to enhance the exposure. Working through the carotid-oculomotor space, the posterior communicating artery was traced back to the posterior cerebral artery. The basilar artery was temporarily occluded for aneurysm dissection after burst suppression to protect the brain. The aneurysm was irregular, multilobulated, and projecting upward. The dominant thalamoperforate artery (artery of Percheron) was arising from the right P1, and densely adherent to the sac of the aneurysm. After dissection of the artery of Percheron away from the aneurysm, it was completely occluded by a side-curved titanium clip. The patient had right oculomotor nerve paresis and headache postoperatively, but at discharge 2 wk later the headache and paresis had completely resolved. The postoperative IADSA showed total occlusion of the aneurysm with patency of the artery of Percheron.This 3-dimensional video shows the technical nuances of microsurgical clipping of a ruptured basilar apex aneurysm and intraoperative dissection of the artery of Percheron.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 30407554 [PubMed - as supplied by publisher]

Disseminated Tuberculosis Presenting as Chronic Orchiepididymitis in a Military Trainee: A Case Report and Review of the Literature.

Case Rep Infect Dis. 2018;2018:7316097

Authors: Williams MU, Burris A, Zingalis A, Lindholm DA, White BK

Abstract
Orchiepididymitis is a clinical diagnosis. The acute form secondary to sexually transmitted or enteric pathogens is well known to primary care providers. However, chronic orchiepididymitis may be secondary to genitourinary tuberculosis (TB), and physicians in countries with a low prevalence of TB might not consider it in their differential diagnosis. Indeed, cognitive errors, such as anchoring or availability bias, may contribute to a delayed diagnosis of genitourinary TB. We present a case of chronic orchiepididymitis as a result of disseminated TB in a Cameroonian male who was visiting the United States for military training. He experienced diagnostic delay and was ultimately diagnosed by orchiectomy. Early consideration of a diagnosis of TB for chronic or recurrent orchiepididymitis in a patient with epidemiologic risk factors is of utmost importance because delayed diagnosis could lead to organ loss.

PMID: 30402306 [PubMed]

ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection.

ACS Infect Dis. 2019 05 10;5(5):725-737

Authors: Thi EP, Dhillon AP, Ardzinski A, Bidirici-Ertekin L, Cobarrubias KD, Cuconati A, Kondratowicz AS, Kwak K, Li AHL, Miller A, Pasetka C, Pei L, Phelps JR, Snead NM, Wang X, Ye X, Sofia MJ, Lee ACH

Abstract
Current approved nucleoside analogue treatments for chronic hepatitis B virus (HBV) infection are effective at controlling viral titer but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control. ARB-1740 is a clinical stage RNA interference agent composed of three siRNAs delivered using lipid nanoparticle technology. In a number of cell and animal models of HBV, ARB-1740 caused HBV RNA reduction, leading to inhibition of multiple elements of the viral life cycle including HBsAg, HBeAg, and HBcAg viral proteins as well as replication marker HBV DNA. ARB-1740 demonstrated pan-genotypic activity in vitro and in vivo, targeting three distinct highly conserved regions of the HBV genome, and effectively inhibited replication of nucleoside analogue-resistant HBV variants. Combination of ARB-1740 with a capsid inhibitor and pegylated interferon-alpha led to greater liver HBsAg reduction which correlated with more robust induction of innate immune responses in a human chimeric mouse model of HBV. The preclinical profile of ARB-1740 demonstrates the promise of RNA interference and HBV antigen reduction in treatment strategies driving toward a cure for HBV.

PMID: 30403127 [PubMed - indexed for MEDLINE]

Acute Post-Traumatic Sleep May Define Vulnerability to a Second Traumatic Brain Injury in Mice.

J Neurotrauma. 2019 04 15;36(8):1318-1334

Authors: Rowe RK, Harrison JL, Morrison HW, Subbian V, Murphy SM, Lifshitz J

Abstract
Chronic neurological impairments can manifest from repetitive traumatic brain injury (rTBI), particularly when subsequent injuries occur before the initial injury completely heals. Herein, we apply post-traumatic sleep as a physiological biomarker of vulnerability, hypothesizing that a second TBI during post-traumatic sleep worsens neurological and histological outcomes compared to one TBI or a second TBI after post-traumatic sleep subsides. Mice received sham or diffuse TBI by midline fluid percussion injury; brain-injured mice received one TBI or rTBIs at 3- or 9-h intervals. Over 40 h post-injury, injured mice slept more than shams. Functional assessments indicated lower latencies on rotarod and increased Neurological Severity Scores for mice with rTBIs within 3 h. Anxiety-like behaviors in the open field task were increased for mice with rTBIs at 3 h. Based on pixel density of silver accumulation, neuropathology was greater at 28 days post-injury (DPI) in rTBI groups than sham and single TBI. Cortical microglia morphology was quantified and mice receiving rTBI were de-ramified at 14 DPI compared to shams and mice receiving a single TBI, suggesting robust microglial response in rTBI groups. Orexin-A-positive cells were sustained in the lateral hypothalamus with no loss detected, indicating that loss of wake-promoting neurons did not contribute to post-traumatic sleep. Thus, duration of post-traumatic sleep is a period of vulnerability that results in exacerbated injury from rTBI. Monitoring individual post-traumatic sleep is a potential clinical tool for personalized TBI management, where regular sleep patterns may inform rehabilitative strategies and return-to-activity guidelines.

PMID: 30398389 [PubMed - indexed for MEDLINE]