Moving from late to early stage disease: lessons learned from erlotinib in pancreatic cancer.
Hepatobiliary Surg Nutr. 2018 Oct;7(5):406-408
Authors: Ko AH
PMID: 30498720 [PubMed]
Long-term therapeutic effect of cell therapy on improvement in erectile function in a rat model with pelvic neurovascular injury.
BJU Int. 2019 07;124(1):145-154
Authors: Gu X, Shi H, Matz E, Zhong L, Long T, Clouse C, Li W, Chen D, Chung H, Murphy S, Yoo J, Lin G, Lue T, Atala A, Jackson J, Zhang Y
Abstract
OBJECTIVE: To determine the long-term therapeutic effect amongst three human cell types on erectile function recovery in a rat model of dual neurovascular-injury erectile dysfunction (NVED).
MATERIALS AND METHODS: A dual NVED model was established in athymic rats by crushing the bilateral cavernous nerves and ligating the bilateral internal pudendal neurovascular bundles. At the time of defect creation, three different types of human cell populations (2.5 × 106 cells/0.2 mL: umbilical vein endothelial cells, adipose-derived stem cells, and amniotic fluid-derived stem cells) were injected intracavernously into the penile tissue. Saline injection (0.2 mL) served as a control group. Erectile function and histomorphological analyses of penile tissues were assessed 12 weeks after defect creation and cell or saline injection.
RESULTS: The ratio of intracavernous pressure to mean arterial pressure (functional indicator) was significantly higher in the cell therapy groups compared to the saline-injected control group (P < 0.05). Immunofluorescence staining showed more cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy groups when compared to the control group.
CONCLUSIONS: Cell therapy enhanced erectile function and ameliorated the histological changes 12 weeks after pelvic neurovascular injury in vivo, indicating that cell therapy may improve the long-term outcomes in neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED.
PMID: 30499626 [PubMed - indexed for MEDLINE]
Wearable Activity Technology And Action-Planning (WATAAP) to promote physical activity in cancer survivors: Randomised controlled trial protocol.
Int J Clin Health Psychol. 2018 May-Aug;18(2):124-132
Authors: Maxwell-Smith C, Cohen PA, Platell C, Tan P, Levitt M, Salama P, Makin GB, Tan J, Salfinger S, Kader Ali Mohan GR, Kane RT, Hince D, Jiménez-Castuera R, Hardcastle SJ
Abstract
Background/Objective: Colorectal and gynecologic cancer survivors are at cardiovascular risk due to comorbidities and sedentary behaviour, warranting a feasible intervention to increase physical activity. The Health Action Process Approach (HAPA) is a promising theoretical framework for health behaviour change, and wearable physical activity trackers offer a novel means of self-monitoring physical activity for cancer survivors. Method: Sixty-eight survivors of colorectal and gynecologic cancer will be randomised into 12-week intervention and control groups. Intervention group participants will receive: a Fitbit Alta™ to monitor physical activity, HAPA-based group sessions, booklet, and support phone-call. Participants in the control group will only receive the HAPA-based booklet. Physical activity (using accelerometers), blood pressure, BMI, and HAPA constructs will be assessed at baseline, 12-weeks (post-intervention) and 24-weeks (follow-up). Data analysis will use the Group x Time interaction from a General Linear Mixed Model analysis. Conclusions: Physical activity interventions that are acceptable and have robust theoretical underpinnings show promise for improving the health of cancer survivors.
PMID: 30487917 [PubMed]
Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma.
Sci Rep. 2018 01 19;8(1):1180
Authors: Connolly NP, Shetty AC, Stokum JA, Hoeschele I, Siegel MB, Miller CR, Kim AJ, Ho CY, Davila E, Simard JM, Devine SE, Rossmeisl JH, Holland EC, Winkles JA, Woodworth GF
Abstract
Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.
PMID: 29352201 [PubMed - indexed for MEDLINE]
A Randomized Study of Exercise and Fitness Trackers in Obese Patients After Total Knee Arthroplasty.
Orthop Clin North Am. 2019 Jan;50(1):35-45
Authors: Smith WA, Zucker-Levin A, Mihalko WM, Williams M, Loftin M, Gurney JG
Abstract
Functional limitations persist in obese patients after total knee arthroplasty (TKA). This study assessed the effect of an exercise program (EP) and fitness trackers (FT) in obese patients with TKA. Sixty patients 1 year after orthopedic surgery were recruited and received a 16-week tailored EP; half were randomized to receive an FT. FT had no measurable effect compared with EP alone. EP improved knee range of motion, strength, and quality-of-life scores. This study provides preliminary evidence that a 16-week EP in obese individuals 1 year post TKA is feasible and effective in improving function and quality of life.
PMID: 30477705 [PubMed - in process]
β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions.
Nat Commun. 2017 02 01;8:14295
Authors: Zhu L, Almaça J, Dadi PK, Hong H, Sakamoto W, Rossi M, Lee RJ, Vierra NC, Lu H, Cui Y, McMillin SM, Perry NA, Gurevich VV, Lee A, Kuo B, Leapman RD, Matschinsky FM, Doliba NM, Urs NM, Caron MG, Jacobson DA, Caicedo A, Wess J
Abstract
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.
PMID: 28145434 [PubMed - indexed for MEDLINE]
The Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in severe traumatic brain injury: a single-centre hybrid implementation and effectiveness study.
Lancet Child Adolesc Health. 2019 01;3(1):23-34
Authors: Vavilala MS, King MA, Yang JT, Erickson SL, Mills B, Grant RM, Blayney C, Qiu Q, Chesnut RM, Jaffe KM, Weiner BJ, Johnston BD
Abstract
BACKGROUND: As far as we know, there are no tested in-hospital care programmes for paediatric traumatic brain injury. We aimed to assess implementation and effectiveness of the Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in children with severe traumatic brain injury.
METHODS: We did a prospective hybrid implementation and effectiveness study at the Harborview Medical Center (Seattle, WA, USA). We included children (aged <18 years) with traumatic brain injury (trauma mechanism and image findings). We assessed service provision, adherence to three key performance indicators, and discharge outcomes associated with the PEGASUS programme. The three key performance indicators were early initiation of enteral (oral or tube feeds) or parenteral nutrition; avoidance of any unwanted hypocarbia (PaCO2 <30 mm Hg) without brain herniation; and maintenance of cerebral perfusion pressure (>40 mm Hg) for 72 h after the diagnosis of severe traumatic brain injury. Poisson regression with robust standard errors was used to estimate the association between adhering to key performance indicators and discharge outcomes.
FINDINGS: Between May 1, 2011, and July 1, 2017, 199 children (median age 11·9 years [IQR 3·4-16·1]) participated in the PEGASUS programme, of whom 193 (97%) had severe traumatic brain injury and six (3%) had moderate traumatic brain injury. 105 patients contributed data for all three key performance indicators. Adherence to at least one key performance indicator was achieved by 101 (96%) of 105 participants, and 44 (42%) achieved adherence to all three key performance indicators. Programme participants achieved adherence to the key performance indicators of hypocarbia (76 of 105 [72%]), nutrition (162 of 199 [81%]), and cerebral perfusion pressure (128 of 199 [64%]). Adherence to the nutrition key performance indicator was associated with higher discharge survival (relative risk [RR] 2·70, 95% CI 1·54-4·73) and a more favourable discharge disposition (3·05, 1·52-6·11). Adherence to the cerebral perfusion pressure key performance indicator was also associated with higher discharge survival (RR 1·33, 95% CI 1·12-1·59) and favourable disposition (1·53, 1·19-1·96). Adherence to each additional key performance indicator was associated with higher survival (RR 1·27, 1·12-1·44) and a more favourable discharge disposition (1·46, 1·23-1·72), in a dose-response manner.
INTERPRETATION: The multilevel, hospital-wide, high-fidelity PEGASUS programme might benefit children and adolescents admitted to the emergency department with severe traumatic brain injury. Cerebral perfusion pressure, nutrition, and hypocarbia targets are essential components of the PEGASUS programme and are associated with favourable discharge outcomes.
FUNDING: National Institutes of Health.
PMID: 30473440 [PubMed - indexed for MEDLINE]
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]
