Frequency doubling technology perimetry for detection of visual field progression in glaucoma: a pointwise linear regression analysis.

PubMed

Liu, Shu; Yu, Marco; Weinreb, Robert N; Lai, Gilda; Lam, Dennis Shun-Chiu; Leung, Christopher Kai-Shun

2014-05-02

We compared the detection of visual field progression and its rate of change between standard automated perimetry (SAP) and Matrix frequency doubling technology perimetry (FDTP) in glaucoma. We followed prospectively 217 eyes (179 glaucoma and 38 normal eyes) for SAP and FDTP testing at 4-month intervals for ≥36 months. Pointwise linear regression analysis was performed. A test location was considered progressing when the rate of change of visual sensitivity was ≤-1 dB/y for nonedge and ≤-2 dB/y for edge locations. Three criteria were used to define progression in an eye: ≥3 adjacent nonedge test locations (conservative), any three locations (moderate), and any two locations (liberal) progressed. The rate of change of visual sensitivity was calculated with linear mixed models. Of the 217 eyes, 6.1% and 3.9% progressed with the conservative criteria, 14.5% and 5.6% of eyes progressed with the moderate criteria, and 20.1% and 11.7% of eyes progressed with the liberal criteria by FDTP and SAP, respectively. Taking all test locations into consideration (total, 54 × 179 locations), FDTP detected more progressing locations (176) than SAP (103, P < 0.001). The rate of change of visual field mean deviation (MD) was significantly faster for FDTP (all with P < 0.001). No eyes showed progression in the normal group using the conservative and the moderate criteria. With a faster rate of change of visual sensitivity, FDTP detected more progressing eyes than SAP at a comparable level of specificity. Frequency doubling technology perimetry can provide a useful alternative to monitor glaucoma progression.

Clinical implications from daily physiotherapy examination of 131 acute hamstring injuries and their association with running speed and rehabilitation progression.

PubMed

Whiteley, Rod; van Dyk, Nicol; Wangensteen, Arnlaug; Hansen, Clint

2018-03-01

To investigate the association of daily clinical measures and the progression of rehabilitation and perceived running effort. A cohort of 131 athletes with an MRI-confirmed acute hamstring injury underwent a standardised criteria-based rehabilitation protocol. Descriptive and inferential statistics were used to investigate the association between daily clinical subjective and objective measures and both the progression of rehabilitation and perceived running effort. These measures included different strength, palpation, flexibility and functional tests. Inter-rater and intrarater reliability and minimal detectable change were established for the clinical measures of strength and flexibility by examining measures taken on consecutive days for the uninjured leg. The progression of the daily measures was seen to be non-linear and varied according to the measure. Intra-rater reliability for the strength and flexibility measures were excellent (95% CI ≥0.85 for all measures). Strength (in the outer range position) and flexibility (in maximum hip flexion with active knee extension (MHFAKE) in supine) were best associated with rehabilitation progression and perceived running effort. Additionally, length of pain on palpation was usefully associated with rehabilitation progression. At lower perceived running effort there was a large variation in actual running speed. Daily physical measures of palpation pain, outer range strength, MHFAKE and reported pain during daily activity are useful to inform the progression of rehabilitation. NCT01812564 and NCT02104258. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

[From clinical judgment to linear regression model.

PubMed

Palacios-Cruz, Lino; Pérez, Marcela; Rivas-Ruiz, Rodolfo; Talavera, Juan O

2013-01-01

When we think about mathematical models, such as linear regression model, we think that these terms are only used by those engaged in research, a notion that is far from the truth. Legendre described the first mathematical model in 1805, and Galton introduced the formal term in 1886. Linear regression is one of the most commonly used regression models in clinical practice. It is useful to predict or show the relationship between two or more variables as long as the dependent variable is quantitative and has normal distribution. Stated in another way, the regression is used to predict a measure based on the knowledge of at least one other variable. Linear regression has as it's first objective to determine the slope or inclination of the regression line: Y = a + bx, where "a" is the intercept or regression constant and it is equivalent to "Y" value when "X" equals 0 and "b" (also called slope) indicates the increase or decrease that occurs when the variable "x" increases or decreases in one unit. In the regression line, "b" is called regression coefficient. The coefficient of determination (R 2 ) indicates the importance of independent variables in the outcome.

A Review of Progress in Clinical Photodynamic Therapy

PubMed Central

Huang, Zheng

2005-01-01

Photodynamic therapy (PDT) has received increased attention since the regulatory approvals have been granted to several photosensitizing drugs and light applicators world-wide. Much progress has been seen in basic sciences and clinical photodynamics in recent years. This review will focus on new developments of clinical investigation and discuss the usefulness of various forms of PDT techniques for curative or palliative treatment of malignant and non-malignant diseases. PMID:15896084

Monitoring clinical progression with mitochondrial disease biomarkers

PubMed Central

Steele, Hannah E; Horvath, Rita; Lyon, Jon J; Chinnery, Patrick F

2017-01-01

Abstract Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies. PMID:28969370

Site-level progression of periodontal disease during a follow-up period

PubMed Central

Morozumi, Toshiya; Nakagawa, Taneaki; Sugaya, Tsutomu; Kawanami, Masamitsu; Suzuki, Fumihiko; Takahashi, Keiso; Abe, Yuzo; Sato, Soh; Makino-Oi, Asako; Saito, Atsushi; Takano, Satomi; Minabe, Masato; Nakayama, Yohei; Ogata, Yorimasa; Kobayashi, Hiroaki; Izumi, Yuichi; Sugano, Naoyuki; Ito, Koichi; Sekino, Satoshi; Numabe, Yukihiro; Fukaya, Chie; Yoshinari, Nobuo; Fukuda, Mitsuo; Noguchi, Toshihide; Kono, Tomoo; Umeda, Makoto; Fujise, Osamu; Nishimura, Fusanori; Yoshimura, Atsutoshi; Hara, Yoshitaka; Nakamura, Toshiaki; Noguchi, Kazuyuki; Kakuta, Erika; Hanada, Nobuhiro; Takashiba, Shogo; Amitani, Yasuharu; Yoshie, Hiromasa

2017-01-01

Periodontal disease is assessed and its progression is determined via observations on a site-by-site basis. Periodontal data are complex and structured in multiple levels; thus, applying a summary statistical approach (i.e., the mean) for site-level evaluations results in loss of information. Previous studies have shown the availability of mixed effects modeling. However, clinically beneficial information on the progression of periodontal disease during the follow-up period is not available. We conducted a multicenter prospective cohort study. Using mixed effects modeling, we analyzed 18,834 sites distributed on 3,139 teeth in 124 patients, and data were collected 5 times over a 24-month follow-up period. The change in the clinical attachment level (CAL) was used as the outcome variable. The CAL at baseline was an important determinant of the CAL changes, which varied widely according to the tooth surface. The salivary levels of periodontal pathogens, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were affected by CAL progression. “Linear”- and “burst”-type patterns of CAL progression occurred simultaneously within the same patient. More than half of the teeth that presented burst-type progression sites also presented linear-type progression sites, and most of the progressions were of the linear type. Maxillary premolars and anterior teeth tended to show burst-type progression. The parameters identified in this study may guide practitioners in determining the type and extent of treatment needed at the site and patient levels. In addition, these results show that prior hypotheses concerning "burst" and "linear" theories are not valid. PMID:29206238

Correlation between HIV-1 genotype and clinical progression in HIV/AIDS patients in Surabaya, Indonesia

NASA Astrophysics Data System (ADS)

Rachman, B. E.; Khairunisa, S. Q.; Witaningrum, A. M.; Yunifiar, M. Q.; Nasronudin

2018-03-01

Several factors such as host and viral factors can affect the progression of HIV/AIDS. This study aims to identify the correlation viral factors, especially the HIV-1 subtype with HIV/AIDS progression. Inpatient HIV/AIDS during the period March to September 2017 and willing to participate are included in the study. Historical data of disease and treatment was taken by medical record. Blood samples were amplified, sequenced and undergone phylogenetic analysis. Linear regression analysis was used to estimate beta coefficient (β) and 95%CI of HIV/AIDS progression (measured by the CD4 change rate, ΔCD4 cell count/time span in months).This study has 17 samples. The HIV-1 subtype was dominated by CRF01_AE (81.8%) followed by subtype B (18.2%). There was significant correlation between subtype HIV-1 (p = 0.04) and body mass index (p = 0.038) with HIV/AIDS clinical stage. Many factors were assumed to be correlated with increased rate of CD4, but we only subtype HIV-1 had a significant correlation (p = 0.024) with it. From multivariate analysis, we also found that subtype HIV-1 had a significant correlation (β = 0.788, 95%CI: 17.5-38.6, p = 0.004).

Clinical progression of ocular injury following arsenical vesicant lewisite exposure.

PubMed

Tewari-Singh, Neera; Croutch, Claire R; Tuttle, Richard; Goswami, Dinesh G; Kant, Rama; Peters, Eric; Culley, Tara; Ammar, David A; Enzenauer, Robert W; Petrash, J Mark; Casillas, Robert P; Agarwal, Rajesh

2016-12-01

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

Stereometric parameters change vs. Topographic Change Analysis (TCA) agreement in Heidelberg Retina Tomography III (HRT-3) early detection of clinical significant glaucoma progression.

PubMed

Dascalu, A M; Cherecheanu, A P; Stana, D; Voinea, L; Ciuluvica, R; Savlovschi, C; Serban, D

2014-01-01

to investigate the sensitivity and specificity of the stereometric parameters change analysis vs. Topographic Change Analysis in early detection of glaucoma progression. 81 patients with POAG were monitored for 4 years (GAT monthly, SAP at every 6 months, optic disc photographs and HRT3 yearly). The exclusion criteria were other optic disc or retinal pathology; topographic standard deviation (TSD>30; inter-test variation of reference height>25 μm. The criterion for structural progression was the following: at least 20 adjacent super-pixels with a clinically significant decrease in height (>5%). 16 patients of the total 81 presented structural progression on TCA. The most useful stereometric parameters for the early detection of glaucoma progression were the following: Rim Area change (sensitivity 100%, specificity 74.2% for a "cut-off " value of -0.05), C/D Area change (sensitivity 85.7%, specificity 71.5% for a "cut off " value of 0.02), C/D linear change (sensitivity 85.7%, specificity 71.5% for a "cut-off " value of 0.02), Rim Volume change (sensitivity 71.4%, specificity 88.8% for a "cut-off " value of -0.04). RNFL Thickness change (<0) was highly sensitive (82%), but less specific for glaucoma progression (45,2%). Changes of the other stereometric parameters have a limited diagnostic value for the early detection of glaucoma progression. TCA is a valuable tool for the assessment of the structural progression in glaucoma patients and its inter-test variability is low. On long-term, the quantitative analysis according to stereometric parameters change is also very important. The most relevant parameters to detect progression are RA, C/D Area, Linear C/D and RV.

Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria.

PubMed Central

Collins, S J; Ahlskog, J E; Parisi, J E; Maraganore, D M

1995-01-01

All cases examined postmortem at the Mayo Clinic that met the classic neuropathological criteria for progressive supranuclear palsy (PSP) were identified for retrospective clinical analyses. The necropsy material was re-examined by a second neuropathologist to confirm the pathological diagnosis of PSP, yielding 12 cases. A range of clinical signs were documented in these patients, with numerous findings beyond those noted in the original descriptions of this disorder. Atypical clinical findings included absence of supranuclear gaze palsy (two cases), prominent asymmetry (two), arm dystonia (two), upper limb apraxia (two), myoclonus (two), chorea (one), eyelid opening apraxia (one), and respiratory disturbance (one). A definite clinical diagnosis of PSP had been made during life in only eight of the 12 patients. From the retrospective analysis of these 12 cases, a set of clinical criteria were developed for the premortem diagnosis of PSP emphasising differences from other akinetic-rigid disorders. PMID:7876846

Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma.

PubMed

De Moraes, C Gustavo; Liebmann, Jeffrey M; Levin, Leonard A

2017-01-01

Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP-lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12-18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint. Copyright © 2016 Elsevier Ltd. All rights reserved.

Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma

PubMed Central

De Moraes, C. Gustavo; Liebmann, Jeffrey M.; Levin, Leonard A.

2016-01-01

Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP-lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12–18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint. PMID:27773767

Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

PubMed

Patel, Jyoti D; Krilov, Lada; Adams, Sylvia; Aghajanian, Carol; Basch, Ethan; Brose, Marcia S; Carroll, William L; de Lima, Marcos; Gilbert, Mark R; Kris, Mark G; Marshall, John L; Masters, Gregory A; O'Day, Steven J; Polite, Blasé; Schwartz, Gary K; Sharma, Sunil; Thompson, Ian; Vogelzang, Nicholas J; Roth, Bruce J

2014-01-10

Since its founding in 1964, the American Society of Clinical Oncology (ASCO) has been committed to improving cancer outcomes through research and the delivery of quality care. Research is the bedrock of discovering better treatments--providing hope to the millions of individuals who face a cancer diagnosis each year. The studies featured in "Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology" represent the invaluable contributions of thousands of patients who participate in clinical trials and the scientists who conduct basic and clinical research. The insights described in this report, such as how cancers hide from the immune system and why cancers may become resistant to targeted drugs, enable us to envision a future in which cancer will be even more controllable and preventable. The scientific process is thoughtful, deliberate, and sometimes slow, but each advance, while helping patients, now also points toward new research questions and unexplored opportunities. Both dramatic and subtle breakthroughs occur so that progress against cancer typically builds over many years. Success requires vision, persistence, and a long-term commitment to supporting cancer research and training. Our nation's longstanding investment in federally funded cancer research has contributed significantly to a growing array of effective new treatments and a much deeper understanding of the drivers of cancer. But despite this progress, our position as a world leader in advancing medical knowledge and our ability to attract the most promising and talented investigators are now threatened by an acute problem: Federal funding for cancer research has steadily eroded over the past decade, and only 15% of the ever-shrinking budget is actually spent on clinical trials. This dismal reality threatens the pace of progress against cancer and undermines our ability to address the continuing needs of our patients. Despite this

Linear enhancement after radio-frequency ablation for hepatocellular carcinoma: is it a sign of recurrence?

PubMed

Takahashi, Masanori; Maruyama, Hitoshi; Shimada, Taro; Kamezaki, Hidehiro; Okabe, Shinichiro; Kanai, Fumihiko; Yoshikawa, Masaharu; Yokosuka, Osamu

2012-11-01

This prospective study was performed in 179 hepatocellular carcinoma (HCC) lesions treated by radio-frequency ablation (RFA) to explore the clinical outcome of "linear enhancement" on contrast-enhanced sonogram. Thirty-three lesions (18.4%) showed linear enhancement, a linear-shaped positive enhancement in the RFA-treated area. Seventeen of them were followed up with no treatment (remaining 16; dropout in eight, additional RFA in six and ineffective treatment in two) and three lesions (3/17, 17.6%) showed local tumor progression corresponding to linear enhancement at 7, 14, 19 months after RFA. Although there was no significant difference in local recurrence rate between the lesions with (3/17) and without linear enhancement (10/35), local tumor progression inside the ablation zone occurred only in the lesions with linear enhancement. In conclusion, linear enhancement inside the RFA-treated area should be followed up within 7 months because it has a risk of local tumor progression. Histology of linear enhancement and its influence on distant recurrence remain to be solved. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis

PubMed Central

Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A.; Kern, Volker D.; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T.; Romero, Klaus

2017-01-01

Abstract Given the recognition that disease‐modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient‐level longitudinal data of 672 subjects with early‐stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP‐1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed‐effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was –3.16 (90% confidence interval [CI] = –0.96 to –5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. PMID:28749580

Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study

PubMed Central

Catanzaro, Daniele; Schäffer, Alejandro A.; Schwartz, Russell

2016-01-01

Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with Synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints. PMID:26353381

Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study.

PubMed

Catanzaro, Daniele; Shackney, Stanley E; Schaffer, Alejandro A; Schwartz, Russell

2016-01-01

Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints.

[Progress of midfacial fat compartments and related clinical applications].

PubMed

Wen, Lihong; Wang, Jinhuang; Li, Yang; Liu, Dalie

2018-02-01

To review the research progress of midfacial fat compartments, and to thoroughly understand its current state of the anatomy and the aging morphologic characters of midfacial fat compartments, as well as the current status of clinical applications. The recent literature concerning the midfacial fat compartments and related clinical applications were extensively reviewed and analyzed. Midfacial fat layer has been considered as a fusion and a continuous layer, experiencing a global atrophy when aging. As more anatomical researches have done, recent studies have shown that midfacial fat layer is broadly divided into superficial and deep layers, which are both divided into different fat compartments by fascia, ligaments, or muscles. Midfacial fat compartments tend to atrophy with age, specifically in the deep fat compartments while hypertrophy in the superficial fat compartments. Clinical applications show that fat volumetric restoration with deep medial cheek fat and Ristow's space can restore the appearance of midface effectively. In recent years, the researches of midfacial fat compartments have achieved obvious progress, which will provide new ideas and basis for fat volumetric restoration. Corresponding treatments are selected based on different sites and different layers with different aging changes, reshaping a more youthful midface.

Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

PubMed Central

Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

2011-01-01

Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall

HIV-1 Genetic Variability in Cuba and Implications for Transmission and Clinical Progression.

PubMed

Blanco, Madeline; Machado, Liuber Y; Díaz, Héctor; Ruiz, Nancy; Romay, Dania; Silva, Eladio

2015-10-01

INTRODUCTION Serological and molecular HIV-1 studies in Cuba have shown very low prevalence of seropositivity, but an increasing genetic diversity attributable to introduction of many HIV-1 variants from different areas, exchange of such variants among HIV-positive people with several coinciding routes of infection and other epidemiologic risk factors in the seropositive population. The high HIV-1 genetic variability observed in Cuba has possible implications for transmission and clinical progression. OBJECTIVE Study genetic variability for the HIV-1 env, gag and pol structural genes in Cuba; determine the prevalence of B and non-B subtypes according to epidemiologic and behavioral variables and determine whether a relationship exists between genetic variability and transmissibility, and between genetic variability and clinical disease progression in people living with HIV/AIDS. METHODS Using two molecular assays (heteroduplex mobility assay and nucleic acid sequencing), structural genes were characterized in 590 people with HIV-1 (480 men and 110 women), accounting for 3.4% of seropositive individuals in Cuba as of December 31, 2013. Nonrandom sampling, proportional to HIV prevalence by province, was conducted. Relationships between molecular results and viral factors, host characteristics, and patients' clinical, epidemiologic and behavioral variables were studied for molecular epidemiology, transmission, and progression analyses. RESULTS Molecular analysis of the three HIV-1 structural genes classified 297 samples as subtype B (50.3%), 269 as non-B subtypes (45.6%) and 24 were not typeable. Subtype B prevailed overall and in men, mainly in those who have sex with men. Non-B subtypes were prevalent in women and heterosexual men, showing multiple circulating variants and recombinant forms. Sexual transmission was the predominant form of infection for all. B and non-B subtypes were encountered throughout Cuba. No association was found between subtypes and

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

PubMed

Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

2018-01-01

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Assessing progression of clinical reasoning through virtual patients: An exploratory study.

PubMed

Forsberg, Elenita; Ziegert, Kristina; Hult, Håkan; Fors, Uno

2016-01-01

To avoid test-driven learning, there have been discussions regarding the use of more formative assessments in health care education to promote students' deep learning. Feedback is important in formative assessment, but many students ignore it; therefore, interventions should be introduced which stimulate them to reflect on the new knowledge. The aim for this study was to explore if Virtual Patient (VP)-based formative assessments, in connection with self-evaluations, had an impact on postgraduate pediatric nursing students' development of clinical reasoning abilities. Students' self-evaluations served as the basis for measuring progress. Data was analysed using deductive content analysis. The findings showed a clear progression of the clinical reasoning ability of the students. After the first assessment, the students described feelings of uncertainty and that their knowledge gaps were exposed. At the mid-course assessment the awareness of improved clinical reasoning was obvious and the students were more certain of knowing how to solve the VP cases. In the final assessment, self-efficacy was expressed. VP-based assessments, in connection with self-evaluations, early in the education resulted in a gain of students' own identification of the concept of clinical reasoning, awareness of what to focus on during clinical practice and visualised expected clinical competence. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multi-task linear programming discriminant analysis for the identification of progressive MCI individuals.

PubMed

Yu, Guan; Liu, Yufeng; Thung, Kim-Han; Shen, Dinggang

2014-01-01

Accurately identifying mild cognitive impairment (MCI) individuals who will progress to Alzheimer's disease (AD) is very important for making early interventions. Many classification methods focus on integrating multiple imaging modalities such as magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). However, the main challenge for MCI classification using multiple imaging modalities is the existence of a lot of missing data in many subjects. For example, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, almost half of the subjects do not have PET images. In this paper, we propose a new and flexible binary classification method, namely Multi-task Linear Programming Discriminant (MLPD) analysis, for the incomplete multi-source feature learning. Specifically, we decompose the classification problem into different classification tasks, i.e., one for each combination of available data sources. To solve all different classification tasks jointly, our proposed MLPD method links them together by constraining them to achieve the similar estimated mean difference between the two classes (under classification) for those shared features. Compared with the state-of-the-art incomplete Multi-Source Feature (iMSF) learning method, instead of constraining different classification tasks to choose a common feature subset for those shared features, MLPD can flexibly and adaptively choose different feature subsets for different classification tasks. Furthermore, our proposed MLPD method can be efficiently implemented by linear programming. To validate our MLPD method, we perform experiments on the ADNI baseline dataset with the incomplete MRI and PET images from 167 progressive MCI (pMCI) subjects and 226 stable MCI (sMCI) subjects. We further compared our method with the iMSF method (using incomplete MRI and PET images) and also the single-task classification method (using only MRI or only subjects with both MRI and PET images

Multi-Task Linear Programming Discriminant Analysis for the Identification of Progressive MCI Individuals

PubMed Central

Yu, Guan; Liu, Yufeng; Thung, Kim-Han; Shen, Dinggang

2014-01-01

Accurately identifying mild cognitive impairment (MCI) individuals who will progress to Alzheimer's disease (AD) is very important for making early interventions. Many classification methods focus on integrating multiple imaging modalities such as magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). However, the main challenge for MCI classification using multiple imaging modalities is the existence of a lot of missing data in many subjects. For example, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, almost half of the subjects do not have PET images. In this paper, we propose a new and flexible binary classification method, namely Multi-task Linear Programming Discriminant (MLPD) analysis, for the incomplete multi-source feature learning. Specifically, we decompose the classification problem into different classification tasks, i.e., one for each combination of available data sources. To solve all different classification tasks jointly, our proposed MLPD method links them together by constraining them to achieve the similar estimated mean difference between the two classes (under classification) for those shared features. Compared with the state-of-the-art incomplete Multi-Source Feature (iMSF) learning method, instead of constraining different classification tasks to choose a common feature subset for those shared features, MLPD can flexibly and adaptively choose different feature subsets for different classification tasks. Furthermore, our proposed MLPD method can be efficiently implemented by linear programming. To validate our MLPD method, we perform experiments on the ADNI baseline dataset with the incomplete MRI and PET images from 167 progressive MCI (pMCI) subjects and 226 stable MCI (sMCI) subjects. We further compared our method with the iMSF method (using incomplete MRI and PET images) and also the single-task classification method (using only MRI or only subjects with both MRI and PET images

Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report.

PubMed

Gorno-Tempini, Maria Luisa; Murray, Ryan C; Rankin, Katherine P; Weiner, Michael W; Miller, Bruce L

2004-12-01

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.

Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement.

PubMed

Puschmann, Andreas; Brighina, Laura; Markopoulou, Katerina; Aasly, Jan; Chung, Sun Ju; Frigerio, Roberta; Hadjigeorgiou, Georgios; Kõks, Sulev; Krüger, Rejko; Siuda, Joanna; Wider, Christian; Zesiewicz, Theresa A; Maraganore, Demetrius M

2015-07-01

Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs. Copyright © 2015 Elsevier Ltd. All rights reserved.

CE: Original Research: Creating an Evidence-Based Progression for Clinical Advancement Programs.

PubMed

Burke, Kathleen G; Johnson, Tonya; Sites, Christine; Barnsteiner, Jane

2017-05-01

: Background: The Institute of Medicine (IOM) and the Quality and Safety Education for Nurses (QSEN) project have identified six nursing competencies and supported their integration into undergraduate and graduate nursing curricula nationwide. But integration of those competencies into clinical practice has been limited, and evidence for the progression of competency proficiency within clinical advancement programs is scant. Using an evidence-based approach and building on the competencies identified by the IOM and QSEN, a team of experts at an academic health system developed eight competency domains and 186 related knowledge, skills, and attitudes (KSAs) for professional nursing practice. The aim of our study was to validate the eight identified competencies and 186 related KSAs and determine their developmental progression within a clinical advancement program. Using the Delphi technique, nursing leadership validated the newly identified competency domains and KSAs as essential to practice. Clinical experts from 13 Magnet-designated hospitals with clinical advancement programs then participated in Delphi rounds aimed at reaching consensus on the developmental progression of the 186 KSAs through four levels of clinical advancement. Two Delphi rounds resulted in consensus by the expert participants. All eight competency domains were determined to be essential at all four levels of clinical practice. At the novice level of practice, the experts identified a greater number of KSAs in the domains of safety and patient- and family-centered care. At more advanced practice levels, the experts identified a greater number of KSAs in the domains of professionalism, teamwork, technology and informatics, and continuous quality improvement. Incorporating the eight competency domains and the 186 KSAs into a framework for clinical advancement programs will likely result in more clearly defined role expectations; enhance accountability; and elevate and promote nursing practice

Progressive learning in endoscopy simulation training improves clinical performance: a blinded randomized trial.

PubMed

Grover, Samir C; Scaffidi, Michael A; Khan, Rishad; Garg, Ankit; Al-Mazroui, Ahmed; Alomani, Tareq; Yu, Jeffrey J; Plener, Ian S; Al-Awamy, Mohamed; Yong, Elaine L; Cino, Maria; Ravindran, Nikila C; Zasowski, Mark; Grantcharov, Teodor P; Walsh, Catharine M

2017-11-01

A structured comprehensive curriculum (SCC) that uses simulation-based training (SBT) can improve clinical colonoscopy performance. This curriculum may be enhanced through the application of progressive learning, a training strategy centered on incrementally challenging learners. We aimed to determine whether a progressive learning-based curriculum (PLC) would lead to superior clinical performance compared with an SCC. This was a single-blinded randomized controlled trial conducted at a single academic center. Thirty-seven novice endoscopists were recruited and randomized to either a PLC (n = 18) or to an SCC (n = 19). The PLC comprised 6 hours of SBT, which progressed in complexity and difficulty. The SCC included 6 hours of SBT, with cases of random order of difficulty. Both groups received expert feedback and 4 hours of didactic teaching. Participants were assessed at baseline, immediately after training, and 4 to 6 weeks after training. The primary outcome was participants' performance during their first 2 clinical colonoscopies, as assessed by using the Joint Advisory Group Direct Observation of Procedural Skills assessment tool (JAG DOPS). Secondary outcomes were differences in endoscopic knowledge, technical and communication skills, and global performance in the simulated setting. The PLC group outperformed the SCC group during first and second clinical colonoscopies, measured by JAG DOPS (P < .001). Additionally, the PLC group had superior technical and communication skills and global performance in the simulated setting (P < .05). There were no differences between groups in endoscopic knowledge (P > .05). Our findings demonstrate the superiority of a PLC for endoscopic simulation, compared with an SCC. Challenging trainees progressively is a simple, theory-based approach to simulation whereby the performance of clinical colonoscopies can be improved. (Clinical trial registration number: NCT02000180.). Copyright © 2017 American Society for

Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance.

PubMed

Kee, Young Moon; Kim, Hwan Jin; Kim, Jung Youn; Rhee, Yong Girl

2017-09-01

The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P < 0.05, respectively). The postoperative rate of recurrence was 5.4%. Among the 14 shoulders with preoperative arthritis, 8 (57.1%) showed progression of arthritis at the last follow up. New occurrence or progression of arthritis after the Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P < 0.05, respectively). Preoperative generalized laxity and lateral overhang were associated with glenohumeral arthritis progression after surgery. (all P < 0.05, retrospectively). The Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. Copyright © 2017 The

Short-term in situ shading effectively mitigates linear progression of coral-killing sponge Terpios hoshinota.

PubMed

Thinesh, Thangadurai; Meenatchi, Ramu; Pasiyappazham, Ramasamy; Jose, Polpass Arul; Selvan, Muthamizh; Kiran, George Seghal; Selvin, Joseph

2017-01-01

The coral-killing sponge, Terpios hoshinota is a global invasive species that has conquered coral patches within a short span of time, which has led to a significant decline in living coral cover at various geographical locations. In this study, we surveyed the linear progression and impact of the Terpios invasion on live coral patches along Palk Bay, Indian Ocean, from August 2013 to August 2015. The field inventory revealed an extensive fatality rate of 76% as a result of Terpios outbreak. Experimental findings showed that symbiotic cyanobacteria act as a nutritional factory for the aggressive growth of Terpios. Shading hypothetically impairs the nutritional symbiont of the invasive species: the effect of sunlight on cyanobacterial biomass and its influence on Terpios progression over live coral patches was tested through in situ shading experiments. This study showed that artificial shading with cotton fabric could effectively mitigate sponge growth on live coral without affecting coral homeostasis.

A new approach to measure visual field progression in glaucoma patients using variational bayes linear regression.

PubMed

Murata, Hiroshi; Araie, Makoto; Asaoka, Ryo

2014-11-20

We generated a variational Bayes model to predict visual field (VF) progression in glaucoma patients. This retrospective study included VF series from 911 eyes of 547 glaucoma patients as test data, and VF series from 5049 eyes of 2858 glaucoma patients as training data. Using training data, variational Bayes linear regression (VBLR) was created to predict VF progression. The performance of VBLR was compared against ordinary least-squares linear regression (OLSLR) by predicting VFs in the test dataset. The total deviation (TD) values of test patients' 11th VFs were predicted using TD values from their second to 10th VFs (VF2-10), the root mean squared error (RMSE) associated with each approach then was calculated. Similarly, mean TD (mTD) of test patients' 11th VFs was predicted using VBLR and OLSLR, and the absolute prediction errors compared. The RMSE resulting from VBLR averaged 3.9 ± 2.1 (SD) and 4.9 ± 2.6 dB for prediction based on the second to 10th VFs (VF2-10) and the second to fourth VFs (VF2-4), respectively. The RMSE resulting from OLSLR was 4.1 ± 2.0 (VF2-10) and 19.9 ± 12.0 (VF2-4) dB. The absolute prediction error (SD) for mTD using VBLR was 1.2 ± 1.3 (VF2-10) and 1.9 ± 2.0 (VF2-4) dB, while the prediction error resulting from OLSLR was 1.2 ± 1.3 (VF2-10) and 6.2 ± 6.6 (VF2-4) dB. The VBLR more accurately predicts future VF progression in glaucoma patients compared to conventional OLSLR, especially in short VF series. © ARVO.

Skew-t partially linear mixed-effects models for AIDS clinical studies.

PubMed

Lu, Tao

2016-01-01

We propose partially linear mixed-effects models with asymmetry and missingness to investigate the relationship between two biomarkers in clinical studies. The proposed models take into account irregular time effects commonly observed in clinical studies under a semiparametric model framework. In addition, commonly assumed symmetric distributions for model errors are substituted by asymmetric distribution to account for skewness. Further, informative missing data mechanism is accounted for. A Bayesian approach is developed to perform parameter estimation simultaneously. The proposed model and method are applied to an AIDS dataset and comparisons with alternative models are performed.

Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention.

PubMed

Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A; Clancy, Colleen E; Eckmann, David M; Garbey, Marc; Kassab, Ghassan S; Lochner, Donna R; McCulloch, Andrew D; Tran-Son-Tay, Roger; Trayanova, Natalia A

2016-09-01

Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications.

Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention

PubMed Central

Zhang, Yanhang; Barocas, Victor H.; Berceli, Scott A.; Clancy, Colleen E.; Eckmann, David M.; Garbey, Marc; Kassab, Ghassan S.; Lochner, Donna R.; McCulloch, Andrew D.; Tran-Son-Tay, Roger; Trayanova, Natalia A.

2016-01-01

Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications. PMID:27138523

Towards a Future Linear Collider and The Linear Collider Studies at CERN

ScienceCinema

Heuer, Rolf-Dieter

2018-06-15

During the week 18-22 October, more than 400 physicists will meet at CERN and in the CICG (International Conference Centre Geneva) to review the global progress towards a future linear collider. The 2010 International Workshop on Linear Colliders will study the physics, detectors and accelerator complex of a linear collider covering both the CLIC and ILC options. Among the topics presented and discussed will be the progress towards the CLIC Conceptual Design Report in 2011, the ILC Technical Design Report in 2012, physics and detector studies linked to these reports, and an increasing numbers of common working group activities. The seminar will give an overview of these topics and also CERN’s linear collider studies, focusing on current activities and initial plans for the period 2011-16. n.b: The Council Chamber is also reserved for this colloquium with a live transmission from the Main Auditorium.

Towards a Future Linear Collider and The Linear Collider Studies at CERN

ScienceCinema

Stapnes, Steinar

2017-12-18

During the week 18-22 October, more than 400 physicists will meet at CERN and in the CICG (International Conference Centre Geneva) to review the global progress towards a future linear collider. The 2010 International Workshop on Linear Colliders will study the physics, detectors and accelerator complex of a linear collider covering both the CLIC and ILC options. Among the topics presented and discussed will be the progress towards the CLIC Conceptual Design Report in 2011, the ILC Technical Design Report in 2012, physics and detector studies linked to these reports, and an increasing numbers of common working group activities. The seminar will give an overview of these topics and also CERN’s linear collider studies, focusing on current activities and initial plans for the period 2011-16. n.b: The Council Chamber is also reserved for this colloquium with a live transmission from the Main Auditorium.

A Multi-state Model for Designing Clinical Trials for Testing Overall Survival Allowing for Crossover after Progression

PubMed Central

Xia, Fang; George, Stephen L.; Wang, Xiaofei

2015-01-01

In designing a clinical trial for comparing two or more treatments with respect to overall survival (OS), a proportional hazards assumption is commonly made. However, in many cancer clinical trials, patients pass through various disease states prior to death and because of this may receive treatments other than originally assigned. For example, patients may crossover from the control treatment to the experimental treatment at progression. Even without crossover, the survival pattern after progression may be very different than the pattern prior to progression. The proportional hazards assumption will not hold in these situations and the design power calculated on this assumption will not be correct. In this paper we describe a simple and intuitive multi-state model allowing for progression, death before progression, post-progression survival and crossover after progression and apply this model to the design of clinical trials for comparing the OS of two treatments. For given values of the parameters of the multi-state model, we simulate the required number of deaths to achieve a specified power and the distribution of time required to achieve the requisite number of deaths. The results may be quite different from those derived using the usual PH assumption. PMID:27239255

Magnetic-mediated hyperthermia for cancer treatment: Research progress and clinical trials

NASA Astrophysics Data System (ADS)

Zhao, Ling-Yun; Liu, Jia-Yi; Ouyang, Wei-Wei; Li, Dan-Ye; Li, Li; Li, Li-Ya; Tang, Jin-Tian

2013-10-01

Research progress and frontiers of magnetic-mediated hyperthermia (MMH) are presented, along with clinical trials in Germany, the US, Japan, and China. Special attention is focused on MMH mediated by magnetic nanoparticles, and multifunctional magnetic devices for cancer multimodality treatment are also introduced.

Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort.

PubMed

Holden, Samantha K; Finseth, Taylor; Sillau, Stefan H; Berman, Brian D

2018-01-01

The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Determine progression rates of MDS-UPDRS scores in de novo PD. 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Non-HDL Cholesterol and Triglycerides: Implications for Coronary Atheroma Progression and Clinical Events.

PubMed

Puri, Rishi; Nissen, Steven E; Shao, Mingyuan; Elshazly, Mohamed B; Kataoka, Yu; Kapadia, Samir R; Tuzcu, E Murat; Nicholls, Stephen J

2016-11-01

Non-high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) linearly associated with ΔPAV. Overt PAV progression (ΔPAV>0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (β=0.62; P<0.001) compared with changes in LDLC (β=0.51; P<0.001). Kaplan-Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non

Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical outcomes.

PubMed

Clark, Donald; Nicholls, Stephen J; St John, Julie; Elshazly, Mohamed B; Kapadia, Samir R; Tuzcu, E Murat; Nissen, Steven E; Puri, Rishi

2018-04-21

Utilizing serial intravascular ultrasonography (IVUS), we aimed to exam the association of intra-individual lipid variability, coronary atheroma progression, and clinical outcomes. We performed a post hoc patient-level analysis of nine clinical trials involving 4976 patients with coronary artery disease who underwent serial coronary IVUS in the setting of a range of medical therapies. We assessed the associations between progression in percent atheroma volume (ΔPAV), clinical outcomes, and visit-to-visit lipid variability including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC)/HDL-C, and apolipoprotein B (ApoB). Variability of lipid parameters was measured using intra-individual standard deviation over 3, 6, 12, 18, and 24 months. Atherogenic lipoprotein variability significantly associated with ΔPAV [odds ratio (95% confidence interval; P-value), LDL-C: 1.09 (1.02, 1.17, P = 0.01); non-HDL-C: 1.10 (1.02, 1.18, P = 0.01); TC/HDL-C: 1.14 (1.06, 1.24, P = 0.001); ApoB: 1.13 (1.03, 1.24, P = 0.01)]. Survival curves revealed significant stepwise relationships between cumulative major adverse cardiovascular events and increasing quartiles of atherogenic lipoprotein variability at 24-months follow-up (log-rank P < 0.01 for all lipoproteins except HDL-C). Stronger associations were noted between achieved lipoprotein levels and ΔPAV [LDL-C: 1.27 (1.17, 1.39; P < 0.001); non-HDL-C: 1.32 (1.21, 1.45; P < 0.001); TC/HDL-C: 1.31 (1.19, 1.45; P < 0.001); ApoB: 1.20 (1.07, 1.35; P = 0.003)]. Greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and clinical outcomes, although the association between achieved atherogenic lipoproteins and atheroma progression appears stronger. These data highlight the importance of achieving low and consistent atherogenic lipoprotein levels to promote

Linear regression analysis of survival data with missing censoring indicators.

PubMed

Wang, Qihua; Dinse, Gregg E

2011-04-01

Linear regression analysis has been studied extensively in a random censorship setting, but typically all of the censoring indicators are assumed to be observed. In this paper, we develop synthetic data methods for estimating regression parameters in a linear model when some censoring indicators are missing. We define estimators based on regression calibration, imputation, and inverse probability weighting techniques, and we prove all three estimators are asymptotically normal. The finite-sample performance of each estimator is evaluated via simulation. We illustrate our methods by assessing the effects of sex and age on the time to non-ambulatory progression for patients in a brain cancer clinical trial.

Annual Research Progress Report Fiscal Year 1990. Volume 1. Department of Clinical Investigation (Brooke Army Medical Center)

DTIC Science & Technology

1990-10-01

granulomE , Arch. Dermatol., (in press). Low, G. J. Ionizing radiation-induced pemphigus. Arch. Dermatol., (in press). McCollough, M. L. Dominant...the severity of their headache on a linear pain scale as well as a verbal scale. Patients were questioned as to whether they had received medications...occurred either by phone or in the Neurologist’s office, using the same verbal and linear scales. Progress: In all, six patients were entered into the

Perimetric progression using the Visual Field Index and the Advanced Glaucoma Intervention Study score and its clinical correlations.

PubMed

Gros-Otero, Juan; Castejón, Miguel; Paz-Moreno, Javier; Mikropoulos, Dimitrios; Teus, Miguel

2015-01-01

To evaluate the association between clinical parameters and the diagnosis of progression using VFI (Visual Field Index) and AGIS (Advanced Glaucoma Intervention Study) score in primary open angle glaucoma. Retrospective study of 517 visual fields of 78 eyes with primary open angle glaucoma analyzed with VFI and AGIS score. Clinical data registered included: age, sphere, pachimetry, basal intraocular pressure (IOP), and IOP during the follow up. Only the AGIS score diagnosis of progression was associated with the clinical parameters registered. Among the analyzed data, the mean IOP during follow up (p = 0.0005) and IOP at the third month of follow up (p = 0.004) were statistically associated with progression using the AGIS criteria. The diagnosis of perimetric progression using the AGIS score in the current study was closer to the real functional progression than the diagnosis using the VFI, as the former was associated with known risk factors for progression in glaucoma. Copyright © 2014 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.

Current Progress of siRNA/shRNA Therapeutics in Clinical Trials

PubMed Central

Burnett, John C.; Rossi, John J.; Tiemann, Katrin

2012-01-01

Through a mechanism known as RNA interference (RNAi), small interfering RNA (siRNA) molecules can target complementary mRNA strands for degradation, thus specifically inhibiting gene expression. The ability of siRNAs to inhibit gene expression offers a mechanism that can be exploited for novel therapeutics. Indeed, over the past decade, at least 21 siRNA therapeutics have been developed for more than a dozen diseases, including various cancers, viruses, and genetic disorders. Like other biological drugs, RNAi-based therapeutics often require a delivery vehicle to transport them to the targeted cells. Thus, the clinical advancement of numerous siRNA drugs has relied on the development of siRNA carriers including biodegradable nanoparticles, lipids, bacteria, and attenuated viruses. Most therapies permit systemic delivery of the siRNA drug, while others use ex vivo delivery by autologous cell therapy. For some of the drugs, advancements in bioengineering and nanotechnology have led to improved control of delivery and release of the siRNA. Likewise, progress in molecular biology has allowed for improved design of the siRNA molecules. Here, we provide an overview of siRNA therapeutics in clinical trials, including their clinical progress, the challenges they have encountered, and the future they hold in the treatment of human diseases. PMID:21744502

Analysis of reciprocal creatinine plots by two-phase linear regression.

PubMed

Rowe, P A; Richardson, R E; Burton, P R; Morgan, A G; Burden, R P

1989-01-01

The progression of renal diseases is often monitored by the serial measurement of plasma creatinine. The slope of the linear relation that is frequently found between the reciprocal of creatinine concentration and time delineates the rate of change in renal function. Minor changes in slope, perhaps indicating response to therapeutic intervention, can be difficult to identify and yet be of clinical importance. We describe the application of two-phase linear regression to identify and characterise changes in slope using a microcomputer. The method fits two intersecting lines to the data by computing a least-squares estimate of the position of the slope change and its 95% confidence limits. This avoids the potential bias of fixing the change at a preconceived time corresponding with an alteration in treatment. The program then evaluates the statistical and clinical significance of the slope change and produces a graphical output to aid interpretation.

Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity.

PubMed

Choi, Chan-Bum; Liang, Matthew H; Bae, Sang-Cheol

2016-01-06

Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design.

Current progress of siRNA/shRNA therapeutics in clinical trials.

PubMed

Burnett, John C; Rossi, John J; Tiemann, Katrin

2011-09-01

Through a mechanism known as RNA interference (RNAi), small interfering RNA (siRNA) molecules can target complementary mRNA strands for degradation, thus specifically inhibiting gene expression. The ability of siRNAs to inhibit gene expression offers a mechanism that can be exploited for novel therapeutics. Indeed, over the past decade, at least 21 siRNA therapeutics have been developed for more than a dozen diseases, including various cancers, viruses, and genetic disorders. Like other biological drugs, RNAi-based therapeutics often require a delivery vehicle to transport them to the targeted cells. Thus, the clinical advancement of numerous siRNA drugs has relied on the development of siRNA carriers, including biodegradable nanoparticles, lipids, bacteria, and attenuated viruses. Most therapies permit systemic delivery of the siRNA drug, while others use ex vivo delivery by autologous cell therapy. Advancements in bioengineering and nanotechnology have led to improved control of delivery and release of some siRNA therapeutics. Likewise, progress in molecular biology has allowed for improved design of the siRNA molecules. Here, we provide an overview of siRNA therapeutics in clinical trials, including their clinical progress, the challenges they have encountered, and the future they hold in the treatment of human diseases. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Usefulness of optic nerve ultrasound to predict clinical progression in multiple sclerosis.

PubMed

Pérez Sánchez, S; Eichau Madueño, S; Rus Hidalgo, M; Domínguez Mayoral, A M; Vilches-Arenas, A; Navarro Mascarell, G; Izquierdo, G

2018-03-21

Progressive neuronal and axonal loss are considered the main causes of disability in patients with multiple sclerosis (MS). The disease frequently involves the visual system; the accessibility of the system for several functional and structural tests has made it a model for the in vivo study of MS pathogenesis. Orbital ultrasound is a non-invasive technique that enables various structures of the orbit, including the optic nerve, to be evaluated in real time. We conducted an observational, ambispective study of MS patients. Disease progression data were collected. Orbital ultrasound was performed on all patients, with power set according to the 'as low as reasonably achievable' (ALARA) principle. Optical coherence tomography (OCT) data were also collected for those patients who underwent the procedure. Statistical analysis was conducted using SPSS version 22.0. Disease progression was significantly correlated with ultrasound findings (P=.041 for the right eye and P=.037 for the left eye) and with Expanded Disability Status Scale (EDSS) score at the end of the follow-up period (P=.07 for the right eye and P=.043 for the left eye). No statistically significant differences were found with relation to relapses or other clinical variables. Ultrasound measurement of optic nerve diameter constitutes a useful, predictive factor for the evaluation of patients with MS. Smaller diameters are associated with poor clinical progression and greater disability (measured by EDSS). Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Linear viral load increase of a single HPV-type in women with multiple HPV infections predicts progression to cervical cancer.

PubMed

Depuydt, Christophe E; Thys, Sofie; Beert, Johan; Jonckheere, Jef; Salembier, Geert; Bogers, Johannes J

2016-11-01

Persistent high-risk human papillomavirus (HPV) infection is strongly associated with development of high-grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type-specific viral-load measurements predict the natural history of the infection. In infections with multiple HPV-types, the individual type-specific viral-load profile could distinguish progressing HPV-infections from regressing infections. A case-cohort natural history study was established using samples from untreated women with multiple HPV-infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real-time qPCR-assay (18 HPV-types). Using serial type-specific viral-load measurements (≥3) we calculated HPV-specific slopes and coefficient of determination (R(2) ) by linear regression. For each woman slopes and R(2) were used to calculate which HPV-induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV-types, each single HPV-type generated similar increasing (0.27copies/cell/day) and decreasing (-0.27copies/cell/day) viral-load slopes. In CIN3+, at least one of the HPV-types had a clonal progressive course (R(2)  ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type-specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion-producing infections the RNA-staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly-formed virions. RNA-hybridization patterns matched the calculated ongoing processes measured by R(2) and slope in serial type-specific viral-load measurements preceding the biopsy. In women with multiple HPV-types, serial type-specific viral-load measurements predict the natural history of the

Progression from laparoscopic-assisted to totally laparoscopic distal gastrectomy: comparison of circular stapler (i-DST) and linear stapler (BBT) for intracorporeal anastomosis.

PubMed

Ikeda, Tetsuo; Kawano, Hiroyuki; Hisamatsu, Yuichi; Ando, Koji; Saeki, Hiroshi; Oki, Eiji; Ohga, Takefumi; Kakeji, Yoshihiro; Tsujitani, Shunichi; Kohnoe, Shunji; Maehara, Yoshihiko

2013-01-01

Billroth I (B-I) gastroduodenostomy is an anastomotic procedure that is widely performed after gastric resection for distal gastric cancer. A circular stapler often is used for B-I gastroduodenostomy in open and laparoscopic-assisted distal gastrectomy. Recently, totally laparoscopic distal gastrectomy (TLDG) has been considered less invasive than laparoscopic-assisted gastrectomy, and many institutions performing laparoscopic-assisted distal gastrectomy are trying to progress to TLDG without markedly changing the anastomosis method. The purpose of this report is to introduce the technical details of new methods of intracorporeal gastroduodenostomy using either a circular or linear stapler and to evaluate their technical feasibility and safety. Seventeen patients who underwent TLDG with the intracorporeal double-stapling technique using a circular stapler (n = 7) or the book-binding technique (BBT) using a linear stapler (n = 10) between February 2010 and April 2011 were enrolled in the study. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. There were no intraoperative complications or conversions to open surgery in any of the 17 patients. The usual postoperative complications following gastroduodenostomy, such as anastomotic leakage and stenosis, were not observed. Anastomosis took significantly longer to complete with DST (64 ± 24 min) than with BBT (34 ± 7 min), but more stapler cartridges were needed with BBT than with DST. TLDG using a circular or linear stapler is feasible and safe to perform. DST will enable institutions performing laparoscopic-assisted distal gastrectomy with circular staplers to progress to TLDG without problems, and this progression may be more economical because fewer stapler cartridges are used during surgery. However, if an institution has already been performing δ anastomosis in TLDG but has been experiencing certain issues with δ anastomosis, converting from δ anastomosis to BBT should be

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Progression of Alzheimer disease as measured by Clinical Dementia Rating sum of boxes scores

PubMed Central

Williams, Monique M.; Storandt, Martha; Roe, Catherine M.; Morris, John C.

2013-01-01

Background This study examined rates of dementia progression as ascertained by the Clinical Dementia Rating sum of boxes (CDR-SB) for symptomatic Alzheimer disease (sAD) and assessed participant characteristics as predictors of CDR-SB progression. Methods Participants (n = 792) were enrolled in longitudinal studies at an Alzheimer’s Disease Research Center, received a diagnosis of sAD with a global CDR of 0.5 (n = 466) or 1 (n = 326), and had at least one follow-up assessment. Progression in CDR-SB over time as a function of baseline global CDR was examined. Results A longitudinal increase (p<.0001) in CDR-SB was observed. The annual rate of change in CDR-SB scores was 1.43 (SE=.05) in the CDR 0.5 sample and 1.91 (SE=.07) in the CDR 1 sample. For participants followed from the beginning of the CDR stage, time to progression to a higher global CDR was longer for individuals who were CDR 0.5 (3.75 years; 95% CI 3.18-4.33) than those who were CDR 1 at baseline (2.98 years; 95%CI 2.75-3.22). In the total CDR 0.5 sample, the significant predictors of progression to the next global CDR stage (p<.01) were age at first sAD diagnosis and apolipoprotein E4 genotype. Conclusions The study findings are relevant to sAD clinical trial design and accurate, reliable ascertainment of the effect of disease-modifying treatments. PMID:22858530

PROGRESS IN CLINICAL ENCAPSULATED ISLET XENOTRANSPLANTATION

PubMed Central

Cooper, David K.C.; Matsumoto, Shinichi; Abalovich, Adrian; Itoh, Takeshi; Mourad, Nizar I.; Gianello, Pierre R; Wolf, Eckhard; Cozzi, Emanuele

2016-01-01

At the 2015 combined congress of the CTS, IPITA, and IXA, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics – (i) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (ii) the inflammatory response to encapsulated pig islets, (iii) methods to improve the secretion of insulin by pig islets, (iv) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (v) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (i) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (ii) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (iii) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (iv) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic-engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally-harmonized ethical and regulatory framework. PMID:27482959

Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis.

PubMed

Healy, Brian C; Engler, David; Gholipour, Taha; Weiner, Howard; Bakshi, Rohit; Chitnis, Tanuja

2011-04-15

Identifying predictors of clinical progression in patients with relapsing-remitting multiple sclerosis (RRMS) is complicated in the era of disease modifying therapy (DMT) because patients follow many different DMT regimens. To investigate predictors of progression in a treated RRMS sample, a cohort of RRMS patients was prospectively followed in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB). Enrollment criteria were exposure to either interferon-β (IFN-β, n=164) or glatiramer acetate (GA, n=114) for at least 6 months prior to study entry. Baseline demographic and clinical features were used as candidate predictors of longitudinal clinical change on the Expanded Disability Status Scale (EDSS). We compared three approaches to account for DMT effects in statistical modeling. In all approaches, we analyzed all patients together and stratified based on baseline DMT. Model 1 used all available longitudinal EDSS scores, even those after on-study DMT changes. Model 2 used only clinical observations prior to changing DMT. Model 3 used causal statistical models to identify predictors of clinical change. When all patients were considered using Model 1, patients with a motor symptom as the first relapse had significantly larger change in EDSS scores during follow-up (p=0.04); none of the other clinical or demographic variables significantly predicted change. In Models 2 and 3, results were generally unchanged. DMT modeling choice had a modest impact on the variables classified as predictors of EDSS score change. Importantly, however, interpretation of these predictors is dependent upon modeling choice. Copyright © 2011 Elsevier B.V. All rights reserved.

Which ante mortem clinical features predict progressive supranuclear palsy pathology?

PubMed

Respondek, Gesine; Kurz, Carolin; Arzberger, Thomas; Compta, Yaroslau; Englund, Elisabet; Ferguson, Leslie W; Gelpi, Ellen; Giese, Armin; Irwin, David J; Meissner, Wassilios G; Nilsson, Christer; Pantelyat, Alexander; Rajput, Alex; van Swieten, John C; Troakes, Claire; Josephs, Keith A; Lang, Anthony E; Mollenhauer, Brit; Müller, Ulrich; Whitwell, Jennifer L; Antonini, Angelo; Bhatia, Kailash P; Bordelon, Yvette; Corvol, Jean-Christophe; Colosimo, Carlo; Dodel, Richard; Grossman, Murray; Kassubek, Jan; Krismer, Florian; Levin, Johannes; Lorenzl, Stefan; Morris, Huw; Nestor, Peter; Oertel, Wolfgang H; Rabinovici, Gil D; Rowe, James B; van Eimeren, Thilo; Wenning, Gregor K; Boxer, Adam; Golbe, Lawrence I; Litvan, Irene; Stamelou, Maria; Höglinger, Günter U

2017-07-01

Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Clinical cancer advances 2011: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

PubMed

Vogelzang, Nicholas J; Benowitz, Steven I; Adams, Sylvia; Aghajanian, Carol; Chang, Susan Marina; Dreyer, Zoann Eckert; Janne, Pasi A; Ko, Andrew H; Masters, Greg A; Odenike, Olatoyosi; Patel, Jyoti D; Roth, Bruce J; Samlowski, Wolfram E; Seidman, Andrew D; Tap, William D; Temel, Jennifer S; Von Roenn, Jamie H; Kris, Mark G

2012-01-01

A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real

Clinical inertia causing new or progression of diabetic retinopathy in type 2 diabetes: A retrospective cohort study.

PubMed

Osataphan, Soravis; Chalermchai, Thep; Ngaosuwan, Kanchana

2017-03-01

Clinical inertia is a failure to intensify treatment according to evidence-based guidelines, and can have both short- and long-term adverse effects for type 2 diabetes (T2D). The aim of the present study was to demonstrate the effects of clinical inertia on glycemic control and diabetes-related complications. A retrospective cohort study was conducted at a university-based hospital in Thailand. Medical records were evaluated retrospectively from January 2010 to December 2014. Patients were classified into two groups: clinical inertia and non-inertia. Clinical inertia was defined as failure to initiate insulin within 3 months in patients with HbA1c ≥9 % who were already taking two oral antidiabetic agents. From 1206 records, 98 patients with mean HbA1c of 10.3 % were identified and enrolled in the study. The median follow-up time of these patients was 29.5 months and 68.4 % were classified into the clinical inertia group. The mean (± SD) HbA1c decrement in the clinical inertia and non-inertia groups was 0.82 ± 1.50 % and 3.02 ± 1.80 %, respectively, at 6 months (P < 0.001) and 1.46 ± 1.85 % and 3.04 ± 1.76 %, respectively, at the end of study (P < 0.001). Clinical inertia was associated with a significantly shorter median time to progression of diabetic retinopathy (DR); log rank test, P = 0.02 and a higher incidence of DR progression (10 vs 2.2 cases per 1000 person-months; P = 0.003). The adjusted incidence rate ratio for DR progression in the clinical inertia group was 4.92 (95 % confidence interval 1.11-21.77; P = 0.036). Being treated by general practitioners was the strongest risk factor associated with clinical inertia. Clinical inertia can cause persistently poor glycemic control and speed up the progression of DR in T2D. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

SU-F-T-668: Irradiating Mouse Brain with a Clinical Linear Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-Torres, C

Purpose: To design and construct a “mouse jig” device that would allow for irradiation of the mouse brain with a clinical Varian 6 MeV Linear Accelerator. This device must serve as a head immobilizer, gaseous anesthesia delivery, and radiation bolus concurrently. Methods: The mouse jig was machined out of nylon given that it is inexpensive, easy to machine, and has similar electron density to water. A cylindrical opening with diameter of 16 mm and 40 mm depth was drilled into a nylon block sized 56×56×50 mm (width, length, depth). Additional slots were included in the block for ear bars andmore » a tooth bar to serve as a three-point immobilization device as well as for anesthesia delivery and scavenging. For ease of access when loading the mouse into the holder, there is a removable piece at the top of the block that is 15 mm in depth. This serves a dual purpose, as with the proper extra shielding, the mouse jig could be used with lower linear energy transfer photons with this piece removed. A baseplate was then constructed with five square slots where the mouse jig can securely be inserted plus additional slots that would allow the baseplate to be mounted on a standard lock bar in the treatment couch. This maximizes the reproducibility of placement between imaging and treatment and between treatment sessions. Results: CT imaging and radiation treatment planning was performed that showed acceptable coverage and uniformity of radiation dose in the mouse brain while sparing the throat and eyes. Conclusion: We have designed and manufactured a device that fulfills our criteria allowing us to selectively irradiate the mouse brain with a clinical linear accelerator. This setup will be used for generating mouse models of radiation-induced brain injury.« less

Patients with ALS show highly correlated progression rates in left and right limb muscles.

PubMed

Rushton, David J; Andres, Patricia L; Allred, Peggy; Baloh, Robert H; Svendsen, Clive N

2017-07-11

Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression. A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb. This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent. First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Clinical risk factors associated with incidence and progression of periodontal conditions in pregnant women.

PubMed

Moss, Kevin L; Beck, James D; Offenbacher, Steven

2005-05-01

Few large studies have investigated the progression of periodontal conditions during pregnancy in a comprehensive manner. This study aimed to identify clinical factors that were predictive of incidence/progression of periodontal measures in pregnant women adjusting for relevant predictors. Periodontal examinations were conducted on 891 pregnant women prior to 26 weeks gestational age and within 48 h after delivery. Gingivitis/periodontitis incidence/progression (GPIP) was defined as four plus sites with 2+ mm increase in probing depth (PD) that resulted in PD of at least 4 mm at delivery. Multivariable models including relevant clinical variables and significant covariates were developed. While several clinical measures were significantly associated with the outcome, having >/=10% of sites with bleeding on probing (BOP) and four plus sites with PD >/=4 mm (PD4) were the best two predictors of GPIP (odds ratio (OR)=2.8, 95% confidence interval (CI)=1.8-4.2; OR=2.0, 95% CI=1.4-2.9, respectively), adjusting for maternal race, age, enrollment weight, smoking during pregnancy, marital status, food stamp eligibility, and private health insurance. Multivariable models assessed the impact of BOP on the PD4-GPIP relationship. PD4 was significant in the presence of BOP (low BOP OR=1.3, 95% CI=0.5-3.3; high BOP OR=3.0, 95% CI=2.2-4.3). Enrollment BOP and PD4 were significant predictors of PD in pregnant women, however; PD4 is only a predictor with BOP.

Clinical Commentary: On-Ice Return-to-Hockey Progression After Anterior Cruciate Ligament Reconstruction

PubMed Central

Capin, Jacob J.; Behrns, William; Thatcher, Karen; Arundale, Amelia; Smith, Angela Hutchinson; Snyder-Mackler, Lynn

2017-01-01

SYNOPSIS Limited literature exists pertaining to rehabilitation of ice hockey players seeking to return-to-sport after anterior cruciate ligament reconstruction (ACLR). The purpose of this clinical commentary is to present a criterion-based, return-to-ice hockey progression for athletes after ACLR. First, we review pertinent literature and provide previously published guidelines on general rehabilitation after ACLR. Then, we present a four-phase, on-ice skating progression with objective criteria to initiate each phase. During the early on-ice phase, the athlete is reintroduced to specific demands, including graded exposure to forward, backward, and crossover skating. In the intermediate on-ice phase, the emphasis shifts to developing power and introducing anticipated changes of direction within a controlled environment. During the late on-ice phase, the focus progresses to developing anaerobic endurance and introducing unanticipated changes of direction, but still without other players or contact. Finally, once objective return-to-sport criteria are met, non-contact team drills, outnumbered and even-numbered drills, practices, scrimmages, and games are progressively reintroduced during the return-to-sport phase. Recommendations for off-ice strength and conditioning exercises complement the on-ice progression. Additionally, we apply the return-to-hockey progression framework to a case report of a female collegiate defensive ice hockey player who returned to sport successfully after ACLR. This criterion-based return-to-hockey progression may guide rehabilitation specialists managing athletes returning to ice hockey after ACLR. PMID:28355976

Linear immunoglobulin A dermatosis mimicking toxic epidermal necrolysis: a case report of etanercept treatment.

PubMed

Prieto-Barrios, M; Velasco-Tamariz, V; Tous-Romero, F; Burillo-Martinez, S; Zarco-Olivo, C; Rodriguez-Peralto, J L; Ortiz-Romero, P L

2018-03-01

A 65-year-old pluripathological woman attended our hospital with a cutaneous eruption of sudden appearance after vancomycin treatment. She presented targetoid lesions affecting approximately 25-30% of her body surface, large erosions with mucosal lesions and positive Nikolsky sign. Under the initial clinical suspicion of toxic epidermal necrolysis (TEN), and considering the recent literature of successful use of etanercept in these cases, she was treated with a single dose of this antitumour necrosis factor (anti-TNF) agent. Subsequently, the exanthema progression stopped and resolution of the lesions happened in a few days. Later on, histopathology revealed a subepidermal blister with dense neutrophilic infiltrate and linear deposits of immunoglobulin A (IgA) on the dermoepidermal junction, allowing us to establish the diagnosis of drug-induced linear IgA dermatosis mimicking TEN. Linear IgA dermatosis can have severe clinical manifestations, even mimicking TEN, and can have high mortality, especially in drug-induced cases. We have not found any other report of linear IgA dermatosis treated with etanercept in the English literature. Anti-TNF medications could represent useful therapeutic alternatives in this dermatosis. © 2017 British Association of Dermatologists.

Clinical progression in Parkinson disease and the neurobiology of axons.

PubMed

Cheng, Hsiao-Chun; Ulane, Christina M; Burke, Robert E

2010-06-01

Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

PubMed Central

Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

2016-01-01

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer. PMID:28203301

A boosted optimal linear learner for retinal vessel segmentation

NASA Astrophysics Data System (ADS)

Poletti, E.; Grisan, E.

2014-03-01

Ocular fundus images provide important information about retinal degeneration, which may be related to acute pathologies or to early signs of systemic diseases. An automatic and quantitative assessment of vessel morphological features, such as diameters and tortuosity, can improve clinical diagnosis and evaluation of retinopathy. At variance with available methods, we propose a data-driven approach, in which the system learns a set of optimal discriminative convolution kernels (linear learner). The set is progressively built based on an ADA-boost sample weighting scheme, providing seamless integration between linear learner estimation and classification. In order to capture the vessel appearance changes at different scales, the kernels are estimated on a pyramidal decomposition of the training samples. The set is employed as a rotating bank of matched filters, whose response is used by the boosted linear classifier to provide a classification of each image pixel into the two classes of interest (vessel/background). We tested the approach fundus images available from the DRIVE dataset. We show that the segmentation performance yields an accuracy of 0.94.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

PubMed

Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

2018-05-01

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0

Progress and dilemma of contemporary clinical pharmacology.

PubMed

Herman, Z S

2005-01-01

Owing to the great progress in clinical chemistry connected with utilization of applied mathematics, pharmacokinetics came into being. The unknown objective methods of research of drugs in human were discovered, among them controlled clinical trials (CCT). These new methodologies generated a new clinical discipline called clinical pharmacology (CPH) which has its roots in basic pharmacology but was applied in clinical specialties. This field is very young, recognized by World Health organization in 1970. Up to the 90s several enthusiasts developed quickly CPH. The scope and development of this discipline is presented in the first part of this article. At the end of the 20th century the science on drugs performed in humans was in the center of interest of the public as well as an object of great pressure of pharmaceutical industry, politicians, and the public. These phenomena started to influence CPH, practiced and taught in medical university faculties and patients care, unfavourably. Government, university authorities, non-profit organizations are not interested in supporting objective research in CPH on the highest academic level. The industry considers the mentioned studies as a threat for its profit. CCT was elaborated for objective comparison of effectiveness and efficacy of old (standard) drugs with the new approved substance. The main purpose of this type of study is a rejection of null hypothesis. Since 1990, these trials caused a strong movement toward evidence-based medicine. A few years ago trials were performed in independent academic centers. These studies were in experienced hands of the teams consistent of highly competent specialists of several fields of medicine. These centers contributed to the quality, intellectual rigor and impact of such clinical trials. But as economic pressure increases, this may belong to the past. Actually pharmaceutical companies curtailed the participation of academic centers in CCT to 40%. According to EU Parliament

Clinical and genetic determinants of progression of type 2 diabetes: A DIRECT Study

PubMed Central

Morris, Andrew D; Franks, Paul W; Jennison, Chris; Palmer, Colin NA; Pearson, Ewan R

2014-01-01

Objective The rate at which diabetes progresses following diagnosis of type 2 diabetes is highly variable between individuals. Research Design and Methods We studied 5250 patients with type 2 diabetes using comprehensive electronic medical records on all patients in Tayside, Scotland from 1992 onwards. We investigated the association of clinical, biochemical and genetic factors with the risk of progression of type 2 diabetes from diagnosis to requirement for insulin treatment (defined as insulin treatment or HbA1c ≥8.5%/69 mmol/mol treated with two or more non-insulin diabetes therapies). Results Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride concentrations (Hazard Ratio (HR) 1.28 per mmol/L (95% CI 1.15-1.42)) and lower HDL concentrations (HR 0.70 per mmol/L (95% CI 0.55-0.87)). A high genetic risk score derived from 61 diabetes risk variants was associated with a younger age of diagnosis, a younger age at starting insulin, but was not associated with the progression rate from diabetes to requirement for insulin treatment. Conclusions Increased triacylglyceride and low HDL are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes suggesting a difference in biological process that needs further investigation. PMID:24186880

Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.

PubMed

Adler, N R; McLean, C A; Aung, A K; Goh, M S Y

2017-04-01

Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well-described phenomenon. Most cases of LABD are idiopathic, but some cases are drug-induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin-tazobactam-induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin-tazobactam and the development of LABD. © 2017 British Association of Dermatologists.

Monitoring progression of clinical reasoning skills during health sciences education using the case method - a qualitative observational study.

PubMed

Orban, Kristina; Ekelin, Maria; Edgren, Gudrun; Sandgren, Olof; Hovbrandt, Pia; Persson, Eva K

2017-09-11

Outcome- or competency-based education is well established in medical and health sciences education. Curricula are based on courses where students develop their competences and assessment is also usually course-based. Clinical reasoning is an important competence, and the aim of this study was to monitor and describe students' progression in professional clinical reasoning skills during health sciences education using observations of group discussions following the case method. In this qualitative study students from three different health education programmes were observed while discussing clinical cases in a modified Harvard case method session. A rubric with four dimensions - problem-solving process, disciplinary knowledge, character of discussion and communication - was used as an observational tool to identify clinical reasoning. A deductive content analysis was performed. The results revealed the students' transition over time from reasoning based strictly on theoretical knowledge to reasoning ability characterized by clinical considerations and experiences. Students who were approaching the end of their education immediately identified the most important problem and then focused on this in their discussion. Practice knowledge increased over time, which was seen as progression in the use of professional language, concepts, terms and the use of prior clinical experience. The character of the discussion evolved from theoretical considerations early in the education to clinical reasoning in later years. Communication within the groups was supportive and conducted with a professional tone. Our observations revealed progression in several aspects of students' clinical reasoning skills on a group level in their discussions of clinical cases. We suggest that the case method can be a useful tool in assessing quality in health sciences education.

RETURN TO PLAY PROGRESSION FOR RUGBY FOLLOWING INJURY TO THE LOWER EXTREMITY: A CLINICAL COMMENTARY AND REVIEW OF THE LITERATURE

PubMed Central

Davis, Chelseana C.

2016-01-01

Background & Purpose Rugby requires unique demands from its players. Those involved in rehabilitation and care of these athletes must possess an understanding of both the game and various positions. There have been numerous reports focusing on the physiological demands and biomechanical analyses of various components of gameplay, but no specific progression has been developed to assist clinicians assessing the readiness to return of a player after injury. The purpose of this clinical commentary is to outline testing components, general gameplay guidelines, movement progressions, and sport and position-specific progressions related to rugby gameplay following a lower extremity injury. Description of Topic This commentary provides a recommended progression for clinical use for use in a return to rugby program. It includes metabolic considerations, advanced strengthening exercises, agility exercises, and incorporation of drills specific to the sport of rugby that may be performed with the clinician or with assistance from team members. This progression also includes testing parameters for each phase and guidance for clinicians regarding the ability to gauge readiness to return to sport. Discussion It is essential that an athlete returning to the sport of rugby undertake a guided, graduated return to sport progression to ensure safety and to decrease the risk of re-injury. This proposed return to sport progression outlines key parameters for both the sport as a whole and for various specific positions. Level of Evidence Level 5 – Clinical Commentary, Review of Literature PMID:27104062

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING.

PubMed

Hafler, Brian P

2017-03-01

Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Word-finding difficulty: a clinical analysis of the progressive aphasias

PubMed Central

Rohrer, Jonathan D.; Knight, William D.; Warren, Jane E.; Fox, Nick C.; Rossor, Martin N.; Warren, Jason D.

2008-01-01

The patient with word-finding difficulty presents a common and challenging clinical problem. The complaint of ‘word-finding difficulty’ covers a wide range of clinical phenomena and may signify any of a number of distinct pathophysiological processes. Although it occurs in a variety of clinical contexts, word-finding difficulty generally presents a diagnostic conundrum when it occurs as a leading or apparently isolated symptom, most often as the harbinger of degenerative disease: the progressive aphasias. Recent advances in the neurobiology of the focal, language-based dementias have transformed our understanding of these processes and the ways in which they breakdown in different diseases, but translation of this knowledge to the bedside is far from straightforward. Speech and language disturbances in the dementias present unique diagnostic and conceptual problems that are not fully captured by classical models derived from the study of vascular and other acute focal brain lesions. This has led to a reformulation of our understanding of how language is organized in the brain. In this review we seek to provide the clinical neurologist with a practical and theoretical bridge between the patient presenting with word-finding difficulty in the clinic and the evidence of the brain sciences. We delineate key illustrative speech and language syndromes in the degenerative dementias, compare these syndromes with the syndromes of acute brain damage, and indicate how the clinical syndromes relate to emerging neurolinguistic, neuroanatomical and neurobiological insights. We propose a conceptual framework for the analysis of word-finding difficulty, in order both better to define the patient's complaint and its differential diagnosis for the clinician and to identify unresolved issues as a stimulus to future work. PMID:17947337

Fear of progression.

PubMed

Herschbach, Peter; Dinkel, Andreas

2014-01-01

Fear of progression (or fear of recurrence) is an appropriate, rational response to the real threat of cancer and cancer treatments. However, elevated levels of fear of progression can become dysfunctional, affecting well-being, quality of life, and social functioning. Research has shown that fear of progression is one of the most frequent distress symptoms of patients with cancer and with other chronic diseases. As a clear consensus concerning clinically relevant states of fear of progression is currently lacking, it is difficult to provide a valid estimate of the rate of cancer patients who clearly suffer from fear of progression. However, recent systematic reviews suggest that probably 50 % of cancer patients experience moderate to severe fear of progression. Furthermore, many patients express unmet needs in dealing with the fear of cancer spreading. These results underline the necessity to provide effective psychological treatments for clinical levels of fear of progression. A few psychosocial interventions for treating fear of progression have been developed so far. Our own, targeted intervention study showed that dysfunctional fear of progression can be effectively treated with a brief group therapy.

Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy: A Randomized Clinical Trial.

PubMed

Silva, Marly Conceição; Magalhães, Tiago Augusto; Meira, Zilda Maria Alves; Rassi, Carlos Henrique Reis Esselin; Andrade, Amanda Cristina de Souza; Gutierrez, Paulo Sampaio; Azevedo, Clerio Francisco; Gurgel-Giannetti, Juliana; Vainzof, Mariz; Zatz, Mayana; Kalil-Filho, Roberto; Rochitte, Carlos Eduardo

2017-02-01

In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), interventions reducing the progression of myocardial disease could affect survival. To assess the effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis (MF) identified on cardiovascular magnetic resonance (CMR). A randomized clinical trial conducted in 2 centers included 76 male patients with DMD or BMD undergoing 2 CMR studies with a 2-year interval for ventricular function and MF assessment. In a non-intent-to-treat trial, 42 patients with MF and normal left ventricular ejection fraction (LVEF) were randomized (1:1) to receive or not receive ACE inhibitor therapy. The study was conducted from June 26, 2009, to June 30, 2012. Data analysis was performed from June 30, 2013, to October 3, 2016. Randomization (1:1) to receive or not receive ACE inhibitor therapy. Primary outcome was MF progression from baseline to the 2-year CMR study. Of the 76 male patients included in the study, 70 had DMD (92%) and 6 had BMD (8%); mean (SD) age at baseline was 13.1 (4.4) years. Myocardial fibrosis was present in 55 patients (72%) and LV systolic dysfunction was identified in 13 patients (24%). Myocardial fibrosis at baseline was an independent indicator of lower LVEF at follow-up (coefficient [SE], -0.16 [0.07]; P = .03). Among patients with MF and preserved LVEF (42 [55%]), those randomized (21 patients in each arm) to receive ACE inhibitors demonstrated slower MF progression compared with the untreated group (mean [SD] increase of 3.1% [7.4%] vs 10.0% [6.2%] as a percentage of LV mass; P = .001). In multivariate analysis, ACE inhibitor therapy was an independent indicator of decreased MF progression (coefficient [SE], -4.51 [2.11]; P = .04). Patients with MF noted on CMR had a higher probability of cardiovascular events (event rate, 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P = .04

Clinical and imaging characterization of progressive spastic dysarthria

PubMed Central

Clark, Heather M.; Duffy, Joseph R.; Whitwell, Jennifer L.; Ahlskog, J. Eric; Sorenson, Eric J.; Josephs, Keith A.

2013-01-01

Objective To describe speech, neurological and imaging characteristics of a series of patients presenting with progressive spastic dysarthria (PSD) as the first and predominant sign of a presumed neurodegenerative disease. Methods Participants were 25 patients with spastic dysarthria as the only or predominant speech disorder. Clinical features, pattern of MRI volume loss on voxel-based morphometry, and pattern of hypometabolism with F18-Fluorodeoxyglucose (FDG-PET) scan are described. Results All patients demonstrated speech characteristics consistent with spastic dysarthria, including strained voice quality, slow speaking rate, monopitch and monoloudness, and slow and regular speech alternating motion rates. Eight patients did not have additional neurological findings on examination. Pseudobulbar affect, upper motor neuron pattern limb weakness, spasticity, Hoffman sign and positive Babinski reflexes were noted in some of the remaining patients. Twenty-three patients had electromyographic assessment and none had diffuse motor neuron disease or met El Escorial criteria for ALS. Voxel-based morphometry revealed striking bilateral white matter volume loss, , affecting the motor cortex (BA 4), including the frontoparietal operculum (BA 43) with extension into the middle cerebral peduncle. FDG-PET showed subtle hypometabolism affecting the premotor and motor cortices in some patients, particularly in those who had a disease duration longer than two years. Conclusions We have characterized a neurodegenerative disorder that begins focally with spastic dysarthria due to involvement of the motor and premotor cortex and descending corticospinal and corticobulbar pathways. We propose the descriptive label “progressive spastic dysarthria” to best capture the dominant presenting feature of the syndrome. PMID:24053325

Student Learning of Basis, Span and Linear Independence in Linear Algebra

ERIC Educational Resources Information Center

Stewart, Sepideh; Thomas, Michael O. J.

2010-01-01

One of the earlier, more challenging concepts in linear algebra at university is that of basis. Students are often taught procedurally how to find a basis for a subspace using matrix manipulation, but may struggle with understanding the construct of basis, making further progress harder. We believe one reason for this is because students have…

Recent progress toward the clinical development of new anti-MRSA antibiotics.

PubMed

Long, Timothy E

2003-04-01

The escalation in drug resistance is well documented for methicillin-resistant Staphylococcus aureus (MRSA) and the urgency to discover new antibiotic treatments is more apparent with the growing incidences of vancomycin-intermediate and vancomycin-resistant S aureus. Much of the current research into finding new remedies focuses on chemical modification of existing antibiotics (ie, glycopeptides and cephalosporins) and developing synthetic molecules with novel mechanisms of action (ie, oxazolidinones and N-thiolated b-lactams). This review describes recent progress toward the clinical development of new drug therapies for MRSA.

Advanced statistics: linear regression, part I: simple linear regression.

PubMed

Marill, Keith A

2004-01-01

Simple linear regression is a mathematical technique used to model the relationship between a single independent predictor variable and a single dependent outcome variable. In this, the first of a two-part series exploring concepts in linear regression analysis, the four fundamental assumptions and the mechanics of simple linear regression are reviewed. The most common technique used to derive the regression line, the method of least squares, is described. The reader will be acquainted with other important concepts in simple linear regression, including: variable transformations, dummy variables, relationship to inference testing, and leverage. Simplified clinical examples with small datasets and graphic models are used to illustrate the points. This will provide a foundation for the second article in this series: a discussion of multiple linear regression, in which there are multiple predictor variables.

Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group

PubMed Central

Scher, Howard I.; Halabi, Susan; Tannock, Ian; Morris, Michael; Sternberg, Cora N.; Carducci, Michael A.; Eisenberger, Mario A.; Higano, Celestia; Bubley, Glenn J.; Dreicer, Robert; Petrylak, Daniel; Kantoff, Philip; Basch, Ethan; Kelly, William Kevin; Figg, William D.; Small, Eric J.; Beer, Tomasz M.; Wilding, George; Martin, Alison; Hussain, Maha

2014-01-01

Purpose To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. Methods A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. Results The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. Conclusion PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit. PMID:18309951

Variability of MMP/TIMP and TGF-β1 Receptors throughout the Clinical Progression of Chronic Venous Disease.

PubMed

Serralheiro, Pedro; Novais, António; Cairrão, Elisa; Maia, Cláudio; Costa Almeida, Carlos M; Verde, Ignacio

2017-12-21

Chronic venous disease (CVeD) is a prevalent condition with a significant socioeconomic burden, yet the pathophysiology is only just beginning to be understood. Previous studies concerning the dysregulation of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs)) within the varicose vein wall are inconsistent and disregard clinical progression. Moreover, it is highly plausible that MMP and TIMP expression/activity is affected by transforming growth factor (TGF)-β1 and its signaling receptors (TGFβRs) expression/activity in the vein wall. A case-control study was undertaken to analyze genetic and immunohistochemical differences between healthy ( n = 13) and CVeD (early stages: n = 19; advanced stages: n = 12) great saphenous vein samples. Samples were grouped based on anatomic harvest site and subjected to quantitative polymerase chain reaction for MMP1 , MMP2 , MMP8 , MMP9 , MMP12 , MMP13 , TIMP1 , TIMP2 , TIMP3 , TIMP4 , TGFβR1 , TGFβR2 , and TGFβR3 gene expression analysis, and then to immunohistochemistry for immunolocalization of MMP2, TIMP2, and TGFβR2. Decreased gene expression of MMP12 , TIMP2 , TIMP3 , TIMP4 , and TGFβR2 was found in varicose veins when compared to controls. Regarding CVeD clinical progression, two facts arose: results across anatomical regions were uneven; decreased gene expression of MMP9 and TGFβR3 and increased gene expression of MMP2 and TIMP3 were found in advanced clinical stages. Most immunohistochemistry results for tunica intima were coherent with qPCR results. In conclusion, decreased expression of TGFβRs might suggest a reduction in TGF-β1 participation in the MMP/TIMP imbalance throughout CVeD progression. Further studies about molecular events in the varicose vein wall are required and should take into consideration the venous anatomical region and CVeD clinical progression.

Tectal gliomas: assessment of malignant progression, clinical management, and quality of life in a supposedly benign neoplasm.

PubMed

Mohme, Malte; Fritzsche, Friederike S; Mende, Klaus C; Matschke, Jakob; Löbel, Ulrike; Kammler, Gertrud; Westphal, Manfred; Emami, Pedram; Martens, Tobias

2018-06-01

OBJECTIVE Tectal gliomas constitute a rare and inhomogeneous group of lesions with an uncertain clinical course. Because these supposedly benign tumors are frequently followed up by observation over many years, the authors undertook this analysis of their own case series in an effort to demonstrate that the clinical course is highly variable and that there is a potential for a progressive biology. METHODS Clinical data analysis of 23 cases of tectal glioma (involving 9 children and 14 adults) was performed retrospectively. Radiographic data were analyzed longitudinally and MR images were evaluated for tumor volume, contrast enhancement, and growth progression. Quality of life was assessed using the EORTC BN20 and C30 questionnaires during follow-up in a subgroup of patients. RESULTS The patients' mean age at diagnosis was 29.2 years. The main presenting symptom at diagnosis was hydrocephalus (80%). Six patients were treated by primary tumor resection (26.1%), 3 patients underwent biopsy followed by resection (13.1%), and 3 patients underwent biopsy only (13.1%). For additional treatment of hydrocephalus, 14 patients (60.9%) received shunts and/or endoscopic third ventriculostomy. Radiographic tumor progression was observed in 47.9% of the 23 cases. The mean time between diagnosis and growth progression was 51.5 months, and the mean time to contrast enhancement was 69.7 months. Histopathological analysis was obtained in 12 cases (52.2%), resulting in 5 cases of high-grade glioma (3 cases of glioblastoma multiforme [GBM], grade IV, and 2 of anaplastic astrocytoma, grade III), 5 cases of pilocytic astrocytoma, 1 diffuse astrocytoma, and 1 ganglioglioma. Malignant progression was observed in 2 cases, with 1 case progressing from a diffuse astrocytoma (grade II) to a GBM (grade IV) within a period of 13 years. Quality-of-life measurements demonstrated distinct functional deficits compared to a healthy sample as well as glioma control cohorts. CONCLUSIONS Analysis of

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING

PubMed Central

HAFLER, BRIAN P.

2017-01-01

Purpose Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. Methods A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Results Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Conclusion Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies. PMID:27753762

AFOMP Policy No 5: career progression for clinical medical physicists in AFOMP countries.

PubMed

Round, W H; Stefanoyiannis, A P; Ng, K H; Rodriguez, L V; Thayalan, K; Han, Y; Tang, F; Fukuda, S; Srivastava, R; Krisanachinda, A; Shiau, A C; Deng, X

2015-06-01

This policy statement, which is the fifth of a series of documents being prepared by the Asia-Oceania Federation of Organizations for Medical Physics Professional Development Committee, gives guidance on how clinical medical physicists' careers should progress from their initial training to career end. It is not intended to be prescriptive as in some AFOMP countries career structures are already essentially defined by employment awards and because such matters will vary considerably from country to country depending on local culture, employment practices and legislation. It is intended to be advisory and set out options for member countries and employers of clinical medical physicists to develop suitable career structures.

Chaos theory for clinical manifestations in multiple sclerosis.

PubMed

Akaishi, Tetsuya; Takahashi, Toshiyuki; Nakashima, Ichiro

2018-06-01

Multiple sclerosis (MS) is a demyelinating disease which characteristically shows repeated relapses and remissions irregularly in the central nervous system. At present, the pathological mechanism of MS is unknown and we do not have any theories or mathematical models to explain its disseminated patterns in time and space. In this paper, we present a new theoretical model from a viewpoint of complex system with chaos model to reproduce and explain the non-linear clinical and pathological manifestations in MS. First, we adopted a discrete logistic equation with non-linear dynamics to prepare a scalar quantity for the strength of pathogenic factor at a specific location of the central nervous system at a specific time to reflect the negative feedback in immunity. Then, we set distinct minimum thresholds in the above-mentioned scalar quantity for demyelination possibly causing clinical relapses and for cerebral atrophy. With this simple model, we could theoretically reproduce all the subtypes of relapsing-remitting MS, primary progressive MS, and secondary progressive MS. With the sensitivity to initial conditions and sensitivity to minute change in parameters of the chaos theory, we could also reproduce the spatial dissemination. Such chaotic behavior could be reproduced with other similar upward-convex functions with appropriate set of initial conditions and parameters. In conclusion, by applying chaos theory to the three-dimensional scalar field of the central nervous system, we can reproduce the non-linear outcome of the clinical course and explain the unsolved disseminations in time and space of the MS patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rank-based estimation in the {ell}1-regularized partly linear model for censored outcomes with application to integrated analyses of clinical predictors and gene expression data.

PubMed

Johnson, Brent A

2009-10-01

We consider estimation and variable selection in the partial linear model for censored data. The partial linear model for censored data is a direct extension of the accelerated failure time model, the latter of which is a very important alternative model to the proportional hazards model. We extend rank-based lasso-type estimators to a model that may contain nonlinear effects. Variable selection in such partial linear model has direct application to high-dimensional survival analyses that attempt to adjust for clinical predictors. In the microarray setting, previous methods can adjust for other clinical predictors by assuming that clinical and gene expression data enter the model linearly in the same fashion. Here, we select important variables after adjusting for prognostic clinical variables but the clinical effects are assumed nonlinear. Our estimator is based on stratification and can be extended naturally to account for multiple nonlinear effects. We illustrate the utility of our method through simulation studies and application to the Wisconsin prognostic breast cancer data set.

Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

PubMed

Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

2014-12-01

To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

PubMed

Irvine, Katharine M; Wockner, Leesa F; Shanker, Mihir; Fagan, Kevin J; Horsfall, Leigh U; Fletcher, Linda M; Ungerer, Jacobus P J; Pretorius, Carel J; Miller, Gregory C; Clouston, Andrew D; Lampe, Guy; Powell, Elizabeth E

2016-03-01

Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of antiretroviral therapy on clinical and immunologic disease progression in HIV positive children: One-year follow-up study

PubMed Central

Patel, Ankur; Trivedi, Sangeeta S.; Chudasama, Rajesh K.; Patel, Priyanka K.

2012-01-01

Objective: To study the effect of antiretroviral therapy (ART) on clinical, immunologic, and nutritional progression of disease in human immunodeficiency virus (HIV)-infected children for 1 year. Materials and Methods: The study included 54 children aged 1.5–15 years who registered at the ART center, Surat, from August 2007 to August 2009. During the study period, the children were followed-up at 6 monthly intervals up to 1 year after starting ART. World Health Organization (WHO) clinical staging and CD4 cell count as per national guidelines, and nutritional status were used to measure clinical and immunologic progression of disease up to 1 year. Results: Out of 54 children, mother-to-child transmission was reported in 96.2% children; for 74% of the children, both parents were HIV positive. All the children were classified according to WHO clinical staging into 4 stages and as per CD4 cell count (%), followed up at 6 and 12 months and the benefits with ART reported. At 12 months follow-up, 15% of the study group children had died. Both mean CD4 count and a relative percentage showed significant increase (P < 0.01) in the study group 1 year after ART. Conclusion: The present study reports benefits of ART in terms of clinical and immunologic progression of disease, nutritional status of HIV-infected children after 1 year of ART. PMID:23230384

Numerical Simulations of Laminar Air-Water Flow of a Non-linear Progressive Wave at Low Wind Speed

NASA Astrophysics Data System (ADS)

Wen, X.; Mobbs, S.

2014-03-01

A numerical simulation for two-dimensional laminar air-water flow of a non-linear progressive water wave with large steepness is performed when the background wind speed varies from zero to the wave phase speed. It is revealed that in the water the difference between the analytical solution of potential flow and numerical solution of viscous flow is very small, indicating that both solutions of the potential flow and viscous flow describe the water wave very accurately. In the air the solutions of potential and viscous flows are very different due to the effects of viscosity. The velocity distribution in the airflow is strongly influenced by the background wind speed and it is found that three wind speeds, , (the maximum orbital velocity of a water wave), and (the wave phase speed), are important in distinguishing different features of the flow patterns.

Completed suicide in a case of clinically diagnosed progressive supranuclear palsy.

PubMed

Wiener, Jennifer; Moran, Maria T; Haut, Marc W

2015-08-01

We present the clinical history and the cognitive and behavioral presentations of a male patient with suspected progressive supranuclear palsy (PSP) who fatally shot himself in the head. We believe his act of suicide was the consequence of impulsivity, rather than primary depression or mood disturbance. In cases of suspected PSP and other atypical parkinsonisms, health professionals must be aware of neurobehavioral risk factors for suicide attempts and completions to promote patient safety; however, the literature on this topic is sparse. Our case highlights the potentially lethal consequences of impulsivity and other neuropsychiatric symptoms in PSP and related syndromes.

Embodied, Symbolic and Formal Thinking in Linear Algebra

ERIC Educational Resources Information Center

Stewart, Sepideh; Thomas, Michael O. J.

2007-01-01

Students often find their first university linear algebra experience very challenging. While coping with procedural aspects of the subject, solving linear systems and manipulating matrices, they may struggle with crucial conceptual ideas underpinning them, making it very difficult to progress in more advanced courses. This research has sought to…

Comparison of Standard Automated Perimetry, Short-Wavelength Automated Perimetry, and Frequency-Doubling Technology Perimetry to Monitor Glaucoma Progression

PubMed Central

Hu, Rongrong; Wang, Chenkun; Gu, Yangshun; Racette, Lyne

2016-01-01

Abstract Detection of progression is paramount to the clinical management of glaucoma. Our goal is to compare the performance of standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry in monitoring glaucoma progression. Longitudinal data of paired SAP, SWAP, and FDT from 113 eyes with primary open-angle glaucoma enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. Data from all tests were expressed in comparable units by converting the sensitivity from decibels to unitless contrast sensitivity and by expressing sensitivity values in percent of mean normal based on an independent dataset of 207 healthy eyes with aging deterioration taken into consideration. Pointwise linear regression analysis was performed and 3 criteria (conservative, moderate, and liberal) were used to define progression and improvement. Global mean sensitivity (MS) was fitted with linear mixed models. No statistically significant difference in the proportion of progressing and improving eyes was observed across tests using the conservative criterion. Fewer eyes showed improvement on SAP compared to SWAP and FDT using the moderate criterion; and FDT detected less progressing eyes than SAP and SWAP using the liberal criterion. The agreement between these test types was poor. The linear mixed model showed a progressing trend of global MS overtime for SAP and SWAP, but not for FDT. The baseline estimate of SWAP MS was significantly lower than SAP MS by 21.59% of mean normal. FDT showed comparable estimation of baseline MS with SAP. SWAP and FDT do not appear to have significant benefits over SAP in monitoring glaucoma progression. SAP, SWAP, and FDT may, however, detect progression in different glaucoma eyes. PMID:26886602

Clinical progression, acute urinary retention, prostate-related surgeries, and costs in patients with benign prostatic hyperplasia taking early versus delayed combination 5α-reductase inhibitor therapy and α-blocker therapy: a retrospective analysis.

PubMed

Morlock, Robert; Goodwin, Bridgett; Gomez Rey, Gabriel; Eaddy, Michael

2013-05-01

Two previous retrospective database analyses compared early combination therapy with an α-blocker (AB) and 5-α reductase inhibitor (5-ARI) to delayed combination therapy and found that patients receiving the delayed combination therapy were more likely to have clinical progression, acute urinary retention (AUR), and surgery. Although these studies indicate the clinical benefits of early treatment, both studies failed to take into account important baseline clinical measures, such as prostate-specific antigen (PSA) values. This study was designed to compare clinical and cost differences in men with benign prostatic hyperplasia (BPH) who initiated early versus delayed combination therapy with a 5-ARI + an AB, factoring in baseline PSA values. This retrospective claims data analysis assessed data from >14 million US men with linked medical data, pharmacy data, laboratory results, and enrollment information from January 1, 2000, to December 31, 2009. Men aged 50 or older and treated for BPH with a 5-ARI + an AB were identified. Patients were required to be eligible for services at least 6 months before and 12 months after the index medication date. Patients were assigned to 1 of 2 treatment groups based on therapy (early or delayed) and 3 cohorts based on availability of PSA laboratory values (patients with a PSA value, patients with a PSA value >1.5 and <10, and all patients). Using a logistic model, the likelihood of clinical progression (defined as the occurrence of AUR or prostate surgery) during the 12 months after the date of first prescription fill was compared between BPH patients receiving early versus delayed combination therapy. BPH-related medical costs (excluding pharmacy costs) were assessed using generalized linear models. Among the 13,551 patients identified for study inclusion, the highest risks for clinical progression, AUR, and prostate-related surgery were consistently demonstrated in patients with a PSA >1.5 and <10. Across all 3 cohorts, the

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer

PubMed Central

Rathkopf, Dana E.; Beer, Tomasz M.; Loriot, Yohann; Higano, Celestia S.; Armstrong, Andrew J.; Sternberg, Cora N.; de Bono, Johann S.; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I.

2018-01-01

Importance Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. Results In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0

Methodological quality and reporting of generalized linear mixed models in clinical medicine (2000-2012): a systematic review.

PubMed

Casals, Martí; Girabent-Farrés, Montserrat; Carrasco, Josep L

2014-01-01

Modeling count and binary data collected in hierarchical designs have increased the use of Generalized Linear Mixed Models (GLMMs) in medicine. This article presents a systematic review of the application and quality of results and information reported from GLMMs in the field of clinical medicine. A search using the Web of Science database was performed for published original articles in medical journals from 2000 to 2012. The search strategy included the topic "generalized linear mixed models","hierarchical generalized linear models", "multilevel generalized linear model" and as a research domain we refined by science technology. Papers reporting methodological considerations without application, and those that were not involved in clinical medicine or written in English were excluded. A total of 443 articles were detected, with an increase over time in the number of articles. In total, 108 articles fit the inclusion criteria. Of these, 54.6% were declared to be longitudinal studies, whereas 58.3% and 26.9% were defined as repeated measurements and multilevel design, respectively. Twenty-two articles belonged to environmental and occupational public health, 10 articles to clinical neurology, 8 to oncology, and 7 to infectious diseases and pediatrics. The distribution of the response variable was reported in 88% of the articles, predominantly Binomial (n = 64) or Poisson (n = 22). Most of the useful information about GLMMs was not reported in most cases. Variance estimates of random effects were described in only 8 articles (9.2%). The model validation, the method of covariate selection and the method of goodness of fit were only reported in 8.0%, 36.8% and 14.9% of the articles, respectively. During recent years, the use of GLMMs in medical literature has increased to take into account the correlation of data when modeling qualitative data or counts. According to the current recommendations, the quality of reporting has room for improvement regarding the

Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis

PubMed Central

Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

2015-01-01

Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469

Progressive solitary sclerosis

PubMed Central

Kaufmann, Timothy J.; Weinshenker, Brian G.; Kantarci, Orhun H.; Schmalstieg, William F.; Paz Soldan, M. Mateo; Flanagan, Eoin P.

2016-01-01

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. Results: The patients' median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. PMID:27638926

Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

PubMed

van der Crabben, Saskia N; Harakalova, Magdalena; Brilstra, Eva H; van Berkestijn, Frédérique M C; Hofstede, Floris C; van Vught, Adrianus J; Cuppen, Edwin; Kloosterman, Wigard; Ploos van Amstel, Hans Kristian; van Haaften, Gijs; van Haelst, Mieke M

2014-01-01

Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family. © 2013 Wiley Periodicals, Inc.

Assessing Decline: Visualising Progression in Huntington's Disease using a Clinical Dashboard with Enroll-HD Data.

PubMed

Walker, Thomas; Ghosh, Boyd; Kipps, Christopher

2017-01-01

In Huntington's disease (HD), it remains unclear how symptom severity and rate of symptomatic change relates to age and CAG repeat number (CAGn). It is often difficult for clinicians to assess whether an affected individual's symptoms are progressing at a similar rate to their affected peers, limiting their ability to intervene at the most appropriate time. To develop a clinical dashboard that compares an individual's total motor score (TMS), total functional capacity (TFC) and symbol digit modality test (SDMT) scores against a global cohort, controlling for age and CAGn. The dashboard could then be used by clinicians to identify individuals progressing at a disproportionate rate to his or her peers. Annualised longitudinal clinical assessment scores from the Enroll-HD dataset were used to generate decline trajectories of the global cohort, allowing cross-sectional (TMS n = 734; TFC n = 734; SDMT n = 694) and longitudinal (TMS n = 270; TFC n = 270; SDMT n = 247) comparison with individual clinical symptom rating scores, to assess decline relative to affected peers. An electronic dashboard with a dynamic output display was created that rapidly compares clinical symptom rating scores of a specific individual against affected peers from a global cohort of comparable CAGn. This study shows the potential for use of multi-centre trial data in allowing comparison of the individual to a larger group to facilitate improved decision-making for individual patients. Visualisation of these metrics via a clinical dashboard demonstrates how it may aid identification of those with disproportionate decline, offering potential for intervention at specific critical points in the disease course.

Linear associations between clinically assessed upper motor neuron disease and diffusion tensor imaging metrics in amyotrophic lateral sclerosis.

PubMed

Woo, John H; Wang, Sumei; Melhem, Elias R; Gee, James C; Cucchiara, Andrew; McCluskey, Leo; Elman, Lauren

2014-01-01

To assess the relationship between clinically assessed Upper Motor Neuron (UMN) disease in Amyotrophic Lateral Sclerosis (ALS) and local diffusion alterations measured in the brain corticospinal tract (CST) by a tractography-driven template-space region-of-interest (ROI) analysis of Diffusion Tensor Imaging (DTI). This cross-sectional study included 34 patients with ALS, on whom DTI was performed. Clinical measures were separately obtained including the Penn UMN Score, a summary metric based upon standard clinical methods. After normalizing all DTI data to a population-specific template, tractography was performed to determine a region-of-interest (ROI) outlining the CST, in which average Mean Diffusivity (MD) and Fractional Anisotropy (FA) were estimated. Linear regression analyses were used to investigate associations of DTI metrics (MD, FA) with clinical measures (Penn UMN Score, ALSFRS-R, duration-of-disease), along with age, sex, handedness, and El Escorial category as covariates. For MD, the regression model was significant (p = 0.02), and the only significant predictors were the Penn UMN Score (p = 0.005) and age (p = 0.03). The FA regression model was also significant (p = 0.02); the only significant predictor was the Penn UMN Score (p = 0.003). Measured by the template-space ROI method, both MD and FA were linearly associated with the Penn UMN Score, supporting the hypothesis that DTI alterations reflect UMN pathology as assessed by the clinical examination.

Missing data and censoring in the analysis of progression-free survival in oncology clinical trials.

PubMed

Denne, J S; Stone, A M; Bailey-Iacona, R; Chen, T-T

2013-01-01

Progression-free survival (PFS) is increasingly used as a primary endpoint in oncology clinical trials. However, trial conduct is often such that PFS data on some patients may be partially missing either due to incomplete follow-up for progression, or due to data that may be collected but confounded by patients stopping randomized therapy or starting alternative therapy prior to progression. Regulatory guidance on how to handle these patients in the analysis and whether to censor these patients differs between agencies. We present results of a reanalysis of 28 Phase III trials from 12 companies or institutions performed by the Pharmaceutical Research and Manufacturers Association-sponsored PFS Expert Team. We show that analyses not adhering to the intention-to-treat principle tend to give hazard ratio estimates further from unity and describe several factors associated with this shift. We present illustrative simulations to support these findings and provide recommendations for the analysis of PFS.

Visual field progression in glaucoma: total versus pattern deviation analyses.

PubMed

Artes, Paul H; Nicolela, Marcelo T; LeBlanc, Raymond P; Chauhan, Balwantray C

2005-12-01

To compare visual field progression with total and pattern deviation analyses in a prospective longitudinal study of patients with glaucoma and healthy control subjects. A group of 101 patients with glaucoma (168 eyes) with early to moderately advanced visual field loss at baseline (average mean deviation [MD], -3.9 dB) and no clinical evidence of media opacity were selected from a prospective longitudinal study on visual field progression in glaucoma. Patients were examined with static automated perimetry at 6-month intervals for a median follow-up of 9 years. At each test location, change was established with event and trend analyses of total and pattern deviation. The event analyses compared each follow-up test to a baseline obtained from averaging the first two tests, and visual field progression was defined as deterioration beyond the 5th percentile of test-retest variability at three test locations, observed on three consecutive tests. The trend analyses were based on point-wise linear regression, and visual field progression was defined as statistically significant deterioration (P < 5%) worse than -1 dB/year at three locations, confirmed by independently omitting the last and the penultimate observation. The incidence and the time-to-progression were compared between total and pattern deviation analyses. To estimate the specificity of the progression analyses, identical criteria were applied to visual fields obtained in 102 healthy control subjects, and the rate of visual field improvement was established in the patients with glaucoma and the healthy control subjects. With both event and trend methods, pattern deviation analyses classified approximately 15% fewer eyes as having progressed than did the total deviation analyses. In eyes classified as progressing by both the total and pattern deviation methods, total deviation analyses tended to detect progression earlier than the pattern deviation analyses. A comparison of the changes observed in MD and the

Rapidly Progressive Osteoarthritis: a Review of the Clinical and Radiologic Presentation.

PubMed

Flemming, Donald J; Gustas-French, Cristy N

2017-07-01

The purpose of this paper is to review the distinct clinical and radiographic features that may lead to prompt diagnosis of rapidly progressive osteoarthritis (RPOA) and thus obviate unnecessary and costly diagnostic workup. RPOA is uncommon but is more frequently seen in practice because of the aging population. RPOA is a destructive arthropathy that occurs most commonly in elderly women but can also be seen in patients that have sustained trauma. The dramatic radiologic manifestations of RPOA can lead to diagnostic confusion with other arthropathies, infection, and osteonecrosis. RPOA was originally described in the hip but may also involve the shoulder. The etiology of RPOA is not well understood, but subchondral fracture probably plays a role in the development of dramatic destruction of the joint that is seen in affected patients. Early diagnosis may reduce the complexity of surgical management. RPOA is an uncommon condition that occurs most frequently in elderly woman or in patients who have sustained trauma. Prompt recognition of the clinical and radiologic features of this arthropathy can reduce unnecessary diagnostic workup and complexity of surgical intervention.

Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study

PubMed Central

2014-01-01

Background Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this “first-in-man” approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration NCT01824121 PMID:24438512

Progression of Late-Onset Stargardt Disease.

PubMed

Lambertus, Stanley; Lindner, Moritz; Bax, Nathalie M; Mauschitz, Matthias M; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; den Hollander, Anneke I; Weber, Bernhard H F; Holz, Frank G; van der Wilt, Gert Jan; Fleckenstein, Monika; Hoyng, Carel B

2016-10-01

Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure. We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset ≥ 45 years. We analyzed RPE atrophy progression on fundus autofluorescence and near-infrared reflectance imaging using semiautomated software and a linear mixed model. We performed sample size calculations to assess the power in a simulated 2-year interventional study and assessed visual endpoints using time-to-event analysis. Over time, progression of RPE atrophy was observed (mean: 0.22 mm/year, 95% confidence interval [CI]: 0.19-0.27). By including only patients with bilateral RPE atrophy in a future trial, 32 patients are needed to reach a power of 83.9% (95% CI: 83.1-84.6), assuming a fixed therapeutic effect size of 30%. We found a median interval between disease onset and visual acuity decline to 20/32, 20/80, and 20/200 of 2.74 (95% CI: 0.54-4.41), 10.15 (95% CI: 6.13-11.38), and 11.38 (95% CI: 6.13-13.34) years, respectively. We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.

Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

PubMed

Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

2018-04-01

Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study.

PubMed

Balagopal, Ashwin; Asmuth, David M; Yang, Wei-Teng; Campbell, Thomas B; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R; Lalloo, Umesh G; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B; Semba, Richard D; Thomas, David L; Bollinger, Robert C; Gupta, Amita

2015-10-01

Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.

Pre-cART Elevation of CRP and CD4+ T-cell Immune Activation Associated with HIV Clinical Progression in a Multinational Case-Cohort Study

PubMed Central

Balagopal, Ashwin; Asmuth, David M.; Yang, Wei-Teng; Campbell, Thomas B.; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R.; Lalloo, Umesh G.; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B.; Semba, Richard D.; Thomas, David L.; Bollinger, Robert C.; Gupta, Amita

2015-01-01

Background Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. Methods A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm3; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort–36; main cohort–200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Results Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm3. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96–5.21). Conclusions Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm3 at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART. PMID:26017661

Power Calculations and Placebo Effect for Future Clinical Trials in Progressive Supranuclear Palsy

PubMed Central

Stamelou, Maria; Schöpe, Jakob; Wagenpfeil, Stefan; Ser, Teodoro Del; Bang, Jee; Lobach, Iryna Y.; Luong, Phi; Respondek, Gesine; Oertel, Wolfgang H.; Boxer, Adam L.; Höglinger, Günter U.

2016-01-01

Background Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. Methods We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. Results The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. Conclusions We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. PMID:26948290

Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease.

PubMed

Tedroff, Joakim; Waters, Susanna; Barker, Roger A; Roos, Raymund; Squitieri, Ferdinando

2015-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies.

Declines in arrestin and rhodopsin in the macula with progression of age-related macular degeneration.

PubMed

Ethen, Cheryl M; Feng, Xiao; Olsen, Timothy W; Ferrington, Deborah A

2005-03-01

Biochemical analysis of age-related macular degeneration (AMD) at distinct stages of the disease will help further understanding of the molecular events associated with disease progression. This study was conducted to determine the ability of a new grading system for eye bank eyes, the Minnesota Grading System (MGS), to discern distinct stages of AMD so that retinal region-specific changes in rod photoreceptor protein expression from donors could be determined. Donor eyes were assigned to a specific level of AMD by using the MGS. Expression of the rod photoreceptor proteins rhodopsin and arrestin was evaluated by Western immunoblot analysis in the macular and peripheral regions of the neurosensory retina from donors at different stages of AMD. A significant linear decline in both arrestin and rhodopsin content correlated with progressive MGS levels in the macula. In contrast, the peripheral region showed no significant correlation between MGS level and the content of either protein. The statistically significant relationship between decreasing macular rod photoreceptor proteins and progressive MGS levels of AMD demonstrates the utility of the clinically based MGS to correspond with specific protein changes found at known, progressive stages of degeneration. Future biochemical analysis of clinically characterized donor eyes will further understanding of the pathobiochemistry of AMD.

[Visual field progression in glaucoma: cluster analysis].

PubMed

Bresson-Dumont, H; Hatton, J; Foucher, J; Fonteneau, M

2012-11-01

Visual field progression analysis is one of the key points in glaucoma monitoring, but distinction between true progression and random fluctuation is sometimes difficult. There are several different algorithms but no real consensus for detecting visual field progression. The trend analysis of global indices (MD, sLV) may miss localized deficits or be affected by media opacities. Conversely, point-by-point analysis makes progression difficult to differentiate from physiological variability, particularly when the sensitivity of a point is already low. The goal of our study was to analyse visual field progression with the EyeSuite™ Octopus Perimetry Clusters algorithm in patients with no significant changes in global indices or worsening of the analysis of pointwise linear regression. We analyzed the visual fields of 162 eyes (100 patients - 58 women, 42 men, average age 66.8 ± 10.91) with ocular hypertension or glaucoma. For inclusion, at least six reliable visual fields per eye were required, and the trend analysis (EyeSuite™ Perimetry) of visual field global indices (MD and SLV), could show no significant progression. The analysis of changes in cluster mode was then performed. In a second step, eyes with statistically significant worsening of at least one of their clusters were analyzed point-by-point with the Octopus Field Analysis (OFA). Fifty four eyes (33.33%) had a significant worsening in some clusters, while their global indices remained stable over time. In this group of patients, more advanced glaucoma was present than in stable group (MD 6.41 dB vs. 2.87); 64.82% (35/54) of those eyes in which the clusters progressed, however, had no statistically significant change in the trend analysis by pointwise linear regression. Most software algorithms for analyzing visual field progression are essentially trend analyses of global indices, or point-by-point linear regression. This study shows the potential role of analysis by clusters trend. However, for best

Clinical and MRI correlates of disease progression in a case of nonfluent/agrammatic variant of primary progressive aphasia due to progranulin (GRN) Cys157LysfsX97 mutation.

PubMed

Caso, Francesca; Agosta, Federica; Magnani, Giuseppe; Galantucci, Sebastiano; Spinelli, Edoardo G; Galimberti, Daniela; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

2014-07-15

Little is known about the longitudinal changes of brain damage in patients with sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) and in progranulin (GRN) mutation carriers. This study reports the clinical and MRI longitudinal data of a patient with nfvPPA carrying GRN Cys157LysfsX97 mutation (GRN+). Voxel-based morphometry, tensor-based morphometry and diffusion tensor MRI were applied to evaluate gray matter (GM) and white matter (WM) changes over three years. The prominent clinical feature was motor speech impairment associated with only mild agrammatism. MRI demonstrated a progressive and severe GM atrophy of inferior fronto-insular-temporo-parietal regions with focal damage to frontotemporal and frontoparietal WM connections. This is the first report of longitudinal MRI data in a nfvPPA- GRN+ patient and this report offers new insights into the pathophysiology of the disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Recent developments in linear theta-pinch research: experiment and theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKenna, K.F.; Bartsch, R.R.; Commisso, R.J.

1978-01-01

High energy plasmas offusion interest can be generated in linear theta pinches. However, end losses present a fundamental limitation on the plasma containment time. This paper discusses recent progress in end-loss and end-stoppering experiments and in the theoretical understanding of linear theta-pinch physics.

Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.

PubMed

Weiss, Brian; Widemann, Brigitte C; Wolters, Pamela; Dombi, Eva; Vinks, Alexander; Cantor, Alan; Perentesis, John; Schorry, Elizabeth; Ullrich, Nicole; Gutmann, David H; Tonsgard, James; Viskochil, David; Korf, Bruce; Packer, Roger J; Fisher, Michael J

2015-04-01

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Linear morphoea follows Blaschko's lines.

PubMed

Weibel, L; Harper, J I

2008-07-01

The aetiology of morphoea (or localized scleroderma) remains unknown. It has previously been suggested that lesions of linear morphoea may follow Blaschko's lines and thus reflect an embryological development. However, the distribution of linear morphoea has never been accurately evaluated. We aimed to identify common patterns of clinical presentation in children with linear morphoea and to establish whether linear morphoea follows the lines of Blaschko. A retrospective chart review of 65 children with linear morphoea was performed. According to clinical photographs the skin lesions of these patients were plotted on to standardized head and body charts. With the aid of Adobe Illustrator a final figure was produced including an overlay of all individual lesions which was used for comparison with the published lines of Blaschko. Thirty-four (53%) patients had the en coup de sabre subtype, 27 (41%) presented with linear morphoea on the trunk and/or limbs and four (6%) children had a combination of the two. In 55 (85%) children the skin lesions were confined to one side of the body, showing no preference for either left or right side. On comparing the overlays of all body and head lesions with the original lines of Blaschko there was an excellent correlation. Our data indicate that linear morphoea follows the lines of Blaschko. We hypothesize that in patients with linear morphoea susceptible cells are present in a mosaic state and that exposure to some trigger factor may result in the development of this condition.

Development of clinical recommendations for progressive return to activity after military mild traumatic brain injury: guidance for rehabilitation providers.

PubMed

McCulloch, Karen L; Goldman, Sarah; Lowe, Lynn; Radomski, Mary Vining; Reynolds, John; Shapiro, Rita; West, Therese A

2015-01-01

Previously published mild traumatic brain injury (mTBI) management guidelines provide very general recommendations to return individuals with mTBI to activity. This lack of specific guidance creates variation in military rehabilitation. The Office of the Army Surgeon General in collaboration with the Defense and Veterans Brain Injury Center, a component center of the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, convened an expert working group to review the existing literature and propose clinical recommendations that standardize rehabilitation activity progression following mTBI. A Progressive Activity Working Group consisted of 11 Department of Defense representatives across all service branches, 7 Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury representatives, and 8 academic/research/civilian experts with experience assessing and treating individuals with mTBI for return to activity. An expert working group meeting included the Progressive Activity Working Group and 15 additional subject matter experts. In February 2012, the Progressive Activity Working Group was established to determine the need and purpose of the rehabilitation recommendations. Following literature review, a table was created on the basis of the progression from the Zurich consensus statement on concussion in sport. Issues were identified for discussion with a meeting of the larger expert group during a July 2012 conference. Following development of rehabilitation guidance, the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury coordinated a similar process for military primary care providers. End products for rehabilitation and primary care providers include specific recommendations for return to activity after concussion. A 6-stage progression specifies activities in physical, cognitive, and balance/vestibular domains and allows for resumption of activity for those with low-level or

Predicting Progression from Mild Cognitive Impairment to Alzheimer's Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification

PubMed Central

Korolev, Igor O.; Symonds, Laura L.; Bozoki, Andrea C.

2016-01-01

Background Individuals with mild cognitive impairment (MCI) have a substantially increased risk of developing dementia due to Alzheimer's disease (AD). In this study, we developed a multivariate prognostic model for predicting MCI-to-dementia progression at the individual patient level. Methods Using baseline data from 259 MCI patients and a probabilistic, kernel-based pattern classification approach, we trained a classifier to distinguish between patients who progressed to AD-type dementia (n = 139) and those who did not (n = 120) during a three-year follow-up period. More than 750 variables across four data sources were considered as potential predictors of progression. These data sources included risk factors, cognitive and functional assessments, structural magnetic resonance imaging (MRI) data, and plasma proteomic data. Predictive utility was assessed using a rigorous cross-validation framework. Results Cognitive and functional markers were most predictive of progression, while plasma proteomic markers had limited predictive utility. The best performing model incorporated a combination of cognitive/functional markers and morphometric MRI measures and predicted progression with 80% accuracy (83% sensitivity, 76% specificity, AUC = 0.87). Predictors of progression included scores on the Alzheimer's Disease Assessment Scale, Rey Auditory Verbal Learning Test, and Functional Activities Questionnaire, as well as volume/cortical thickness of three brain regions (left hippocampus, middle temporal gyrus, and inferior parietal cortex). Calibration analysis revealed that the model is capable of generating probabilistic predictions that reliably reflect the actual risk of progression. Finally, we found that the predictive accuracy of the model varied with patient demographic, genetic, and clinical characteristics and could be further improved by taking into account the confidence of the predictions. Conclusions We developed an accurate prognostic model for predicting

Quantifying Disease Progression in Amyotrophic Lateral Sclerosis

PubMed Central

Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

2014-01-01

Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. PMID:25223628

A prospective clinical trial of specialist renal nursing in the primary care setting to prevent progression of chronic kidney: a quality improvement report.

PubMed

Walker, Rachael C; Marshall, Mark R; Polaschek, Nick R

2014-09-20

Early detection and effective management of risk factors can potentially delay progression of chronic kidney disease (CKD) to end-stage kidney disease, and decrease mortality and morbidity from cardiovascular (CV) disease. We evaluated a specialist nurse-led intervention in the primary care setting to address accepted risk factors in a study sample of adults at 'high risk of CKD progression', defined as uncontrolled type II diabetes and/or hypertension and a history of poor clinic attendance. The study was a non-controlled quality improvement study with pre- and post- intervention comparisons to test feasibility and potential effectiveness. Patients within two primary care practices were screened and recruited to the study. Fifty-two patients were enrolled, with 36 completing 12-months follow-up. The intervention involved a series of sessions led by the nephrology Nurse Practitioner with assistance from practice nurses. These sessions included assessment, education and planned medication and lifestyle changes. The primary outcome measured was proteinuria (ACR), and the secondary outcomes estimated glomerular filtration rate (eGFR) and 5-year absolute CV risk. Several 'intermediary' secondary outcomes were also measured including: blood pressure, serum total cholesterol, glycosylated haemoglobin (HbA1c), body mass index (BMI), prevalence of active smoking, a variety of self-management domains, and medication prescription. Analysis of data was performed using linear and logistic regression as appropriate. There was a significant improvement in ACR (average decrease of -6.75 mg/mmol per month) over the course of the study. There was a small but significant decrease in eGFR and a reduction in 5 year absolute CV risk. Blood pressure, serum total cholesterol, and HbA1c all decreased significantly. Adherence to lifestyle advice improved with a significant reduction in prevalence of active smoking, although there was no significant change in BMI. Self

Semantic Memory in the Clinical Progression of Alzheimer Disease.

PubMed

Tchakoute, Christophe T; Sainani, Kristin L; Henderson, Victor W

2017-09-01

Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease. We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year. At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency). The semantic-lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function. Semantic-lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

Achieving progress through clinical governance? A national study of health care managers' perceptions in the NHS in England

PubMed Central

Freeman, T; Walshe, K

2004-01-01

Background: A national cross sectional study was undertaken to explore the perceptions concerning the importance of, and progress in, aspects of clinical governance among board level and directorate managers in English acute, ambulance, and mental health/learning disabilities (MH/LD) trusts. Participants: A stratified sample of acute, ambulance, and mental health/learning disabilities trusts in England (n = 100), from each of which up to 10 board level and 10 directorate level managers were randomly sampled. Methods: Fieldwork was undertaken between April and July 2002 using the Organisational Progress in Clinical Governance (OPCG) schedule to explore managers' perceptions of the importance of, and organisational achievement in, 54 clinical governance competency items in five aggregated domains: improving quality; managing risks; improving staff performance; corporate accountability; and leadership and collaboration. The difference between ratings of importance and achievement was termed a shortfall. Results: Of 1916 individuals surveyed, 1177 (61.4%) responded. The competency items considered most important and recording highest perceived achievement related to corporate accountability structures and clinical risks. The highest shortfalls between perceived importance and perceived achievement were reported in joint working across local health communities, feedback of performance data, and user involvement. When aggregated into domains, greatest achievement was perceived in the assurance related areas of corporate accountability and risk management, with considerably less perceived achievement and consequently higher shortfalls in quality improvement and leadership and collaboration. Directorate level managers' perceptions of achievement were found to be significantly lower than those of their board level colleagues on all domains other than improving performance. No differences were found in perceptions of achievement between different types of trusts, or between

Achieving progress through clinical governance? A national study of health care managers' perceptions in the NHS in England.

PubMed

Freeman, T; Walshe, K

2004-10-01

A national cross sectional study was undertaken to explore the perceptions concerning the importance of, and progress in, aspects of clinical governance among board level and directorate managers in English acute, ambulance, and mental health/learning disabilities (MH/LD) trusts. A stratified sample of acute, ambulance, and mental health/learning disabilities trusts in England (n = 100), from each of which up to 10 board level and 10 directorate level managers were randomly sampled. Fieldwork was undertaken between April and July 2002 using the Organisational Progress in Clinical Governance (OPCG) schedule to explore managers' perceptions of the importance of, and organisational achievement in, 54 clinical governance competency items in five aggregated domains: improving quality; managing risks; improving staff performance; corporate accountability; and leadership and collaboration. The difference between ratings of importance and achievement was termed a shortfall. Of 1916 individuals surveyed, 1177 (61.4%) responded. The competency items considered most important and recording highest perceived achievement related to corporate accountability structures and clinical risks. The highest shortfalls between perceived importance and perceived achievement were reported in joint working across local health communities, feedback of performance data, and user involvement. When aggregated into domains, greatest achievement was perceived in the assurance related areas of corporate accountability and risk management, with considerably less perceived achievement and consequently higher shortfalls in quality improvement and leadership and collaboration. Directorate level managers' perceptions of achievement were found to be significantly lower than those of their board level colleagues on all domains other than improving performance. No differences were found in perceptions of achievement between different types of trusts, or between trusts at different stages in the Commission

Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model

PubMed Central

Scher, Howard I.; Solo, Kirk; Valant, Jason; Todd, Mary B.; Mehra, Maneesha

2015-01-01

Objective To identify patient populations most in need of treatment across the prostate cancer disease continuum, we developed a novel dynamic transition model based on risk of disease progression and mortality. Design and Outcome Measurements We modeled the flow of patient populations through eight prostate cancer clinical states (PCCS) that are characterized by the status of the primary tumor, presence of metastases, prior and current treatment, and testosterone levels. Simulations used published US incidence rates for each year from 1990. Progression and mortality rates were derived from published clinical trials, meta-analyses, and observational studies. Model outputs included the incidence, prevalence, and mortality for each PCCS. The impact of novel treatments was modeled in three distinct scenarios: metastatic castration-resistant prostate cancer (mCRPC), non-metastatic CRPC (nmCRPC), or both. Results and Limitations The model estimated the prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and incidence of mCRPC as 36,100 and 42,970, respectively. All-cause mortality in prostate cancer was estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 19.5% of these deaths, respectively, occurring in men with mCRPC. The majority (86%) of incidence flow into mCRPC states was from the nmCRPC clinical state. In the scenario with novel interventions for nmCRPC states, the progression to mCRPC is reduced, thus decreasing mCRPC incidence by 12% in 2020, with a sustained decline in mCRPC mortality. A limitation of the model is that it does not estimate prostate cancer—specific mortality. Conclusion The model informs clinical trial design for prostate cancer by quantifying outcomes in PCCS, and demonstrates the impact of an effective therapy applied in an earlier clinical state of nmCRPC on the incidence of mCRPC morbidity and subsequent mortality. PMID:26460686

Association between Single Nucleotide Polymorphism of Vitamin D Receptor Gene FokI Polymorphism and Clinical Progress of Benign Prostatic Hyperplasia

PubMed Central

Ruan, Li; Zhu, Jian-guo; Pan, Cong; Hua, Xing; Yuan, Dong-bo; Li, Zheng-ming; Zhong, Wei-de

2015-01-01

Background. The aim of the study was to investigate the association between single nucleotide polymorphism (SNP) of vitamin D receptor (VDR) gene and clinical progress of benign prostatic hyperplasia (BPH) in Chinese men. Methods. The DNA was extracted from blood of 200 BPH patients with operation (progression group) and 200 patients without operation (control group), respectively. The genotypes of VDR gene FokI SNP represented by “F/f” were identified by PCR-restriction fragment length polymorphism. The odds ratio (OR) of having progression of BPH for having the genotype were calculated. Results. Our date indicated that the f alleles of the VDR gene FokI SNP associated with the progression of BPH (P = 0.009). Conclusion. For the first time, our study demonstrated that VDR gene FokI SNP may be associated with the risk of BPH progress. PMID:25685834

Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development.

PubMed

Stahel, R; Bogaerts, J; Ciardiello, F; de Ruysscher, D; Dubsky, P; Ducreux, M; Finn, S; Laurent-Puig, P; Peters, S; Piccart, M; Smit, E; Sotiriou, C; Tejpar, S; Van Cutsem, E; Tabernero, J

2015-02-01

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Correlation between clinical fetal head station and sonographic angle of progression during the second stage of labor.

PubMed

Perlman, Sharon; Kivilevitch, Zvi; Moran, Orit; Katorza, Eldad; Kees, Salim; Achiron, Reuven; Gilboa, Yinon

2017-08-04

To investigate the correlation between the angle of progression and the clinical fetal head station (FHS) during the second stage of labor, and to build reference range. A prospective, observational study was conducted. Women carrying singleton term pregnancies were enrolled during the second stage of labor. FHS was assessed manually by a senior obstetrician, while the angle of progression (AOP) was assessed by transperineal ultrasound (TPU). Both examiners were blinded to each others results. The correlation between the sonographic AOP and the clinical FHS was analyzed. Seventy patients comprised the study group. Clinical FHS demonstrated an excellent correlation with the sonographic measurement of AOP (Pearson's Correlation 0.642, p < 0.001). This correlation was best described by a cubic regression according to the formula: 123.800 + 10.290 × FHS -2.889 * FHS +0.910, (r 2  = 0.423, p < .001). After aggregation of the mean AOP per FHS, the relative predicted centiles values and standard deviation were calculated. The mean Z score between measured and predicted values of the AOP for a given FHS was 0.007 (range -0.13 to +0.006). Our results demonstrate a significant correlation between the clinical FHS and the TPU measured AOP. These standardized sonographic values may serve the obstetrician as a reliable, objective auxiliary tool for the evaluation of the FHS during the second stage of labor.

Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

PubMed

Fox, Robert J; Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-11-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

PubMed Central

Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-01-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. PMID:22917690

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

PubMed Central

Mahr, Benedikt; Granofszky, Nicolas; Muckenhuber, Moritz; Wekerle, Thomas

2017-01-01

The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD) constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long-term patients and progress

Machine Learning Approach for Classifying Multiple Sclerosis Courses by Combining Clinical Data with Lesion Loads and Magnetic Resonance Metabolic Features.

PubMed

Ion-Mărgineanu, Adrian; Kocevar, Gabriel; Stamile, Claudio; Sima, Diana M; Durand-Dubief, Françoise; Van Huffel, Sabine; Sappey-Marinier, Dominique

2017-01-01

Purpose: The purpose of this study is classifying multiple sclerosis (MS) patients in the four clinical forms as defined by the McDonald criteria using machine learning algorithms trained on clinical data combined with lesion loads and magnetic resonance metabolic features. Materials and Methods: Eighty-seven MS patients [12 Clinically Isolated Syndrome (CIS), 30 Relapse Remitting (RR), 17 Primary Progressive (PP), and 28 Secondary Progressive (SP)] and 18 healthy controls were included in this study. Longitudinal data available for each MS patient included clinical (e.g., age, disease duration, Expanded Disability Status Scale), conventional magnetic resonance imaging and spectroscopic imaging. We extract N -acetyl-aspartate (NAA), Choline (Cho), and Creatine (Cre) concentrations, and we compute three features for each spectroscopic grid by averaging metabolite ratios (NAA/Cho, NAA/Cre, Cho/Cre) over good quality voxels. We built linear mixed-effects models to test for statistically significant differences between MS forms. We test nine binary classification tasks on clinical data, lesion loads, and metabolic features, using a leave-one-patient-out cross-validation method based on 100 random patient-based bootstrap selections. We compute F1-scores and BAR values after tuning Linear Discriminant Analysis (LDA), Support Vector Machines with gaussian kernel (SVM-rbf), and Random Forests. Results: Statistically significant differences were found between the disease starting points of each MS form using four different response variables: Lesion Load, NAA/Cre, NAA/Cho, and Cho/Cre ratios. Training SVM-rbf on clinical and lesion loads yields F1-scores of 71-72% for CIS vs. RR and CIS vs. RR+SP, respectively. For RR vs. PP we obtained good classification results (maximum F1-score of 85%) after training LDA on clinical and metabolic features, while for RR vs. SP we obtained slightly higher classification results (maximum F1-score of 87%) after training LDA and SVM-rbf on

Clinical Investigation Program Annual Progress Report.

DTIC Science & Technology

1985-09-30

027 78/114 In Vitro Effect of Minoxidil on Collagen Produc- tion by Normal and Scleroderma Fibroblasts (C) (PR...effect of minoxidil on collagen production Dy normal and scleroderma fibroblasts. Previously titled: The use of minoxidil in treating progressive...Svc: (tO) Assoc Investigators: (11) Key Words: scleroderma, minoxidil Thomas P. O’Barr PhD, DAC fibroblasts, collagen Ellen Swanson MS, DAC Don

Clinical Cancer Advances 2018: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

PubMed

Heymach, John; Krilov, Lada; Alberg, Anthony; Baxter, Nancy; Chang, Susan Marina; Corcoran, Ryan; Dale, William; DeMichele, Angela; Magid Diefenbach, Catherine S; Dreicer, Robert; Epstein, Andrew S; Gillison, Maura L; Graham, David L; Jones, Joshua; Ko, Andrew H; Lopez, Ana Maria; Maki, Robert G; Rodriguez-Galindo, Carlos; Schilsky, Richard L; Sznol, Mario; Westin, Shannon Neville; Burstein, Harold

2018-04-01

A MESSAGE FROM ASCO'S PRESIDENT I remember when ASCO first conceived of publishing an annual report on the most transformative research occurring in cancer care. Thirteen reports later, the progress we have chronicled is remarkable, and this year is no different. The research featured in ASCO's Clinical Cancer Advances 2018 report underscores the impressive gains in our understanding of cancer and in our ability to tailor treatments to tumors' genetic makeup. The ASCO 2018 Advance of the Year, adoptive cell immunotherapy, allows clinicians to genetically reprogram patients' own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy-a type of adoptive cell immunotherapy-has led to remarkable results in young patients with acute lymphoblastic leukemia (ALL) and in adults with lymphoma and multiple myeloma. Researchers are also exploring this approach in other types of cancer. This advance would not be possible without robust federal investment in cancer research. The first clinical trial of CAR T-cell therapy in children with ALL was funded, in part, by grants from the National Cancer Institute (NCI), and researchers at the NCI Center for Cancer Research were the first to report on possible CAR T-cell therapy for multiple myeloma. These discoveries follow decades of prior research on immunology and cancer biology, much of which was supported by federal dollars. In fact, many advances that are highlighted in the 2018 Clinical Cancer Advances report were made possible thanks to our nation's support for biomedical research. Funding from the US National Institutes of Health and the NCI helps researchers pursue critical patient care questions and addresses vital, unmet needs that private industry has little incentive to take on. Federally supported cancer research generates the biomedical innovations that fuel the development and availability of new and improved treatments for patients. We need sustained federal

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy.

PubMed

Piattella, Maria Cristina; Upadhyay, N; Bologna, M; Sbardella, E; Tona, F; Formica, A; Petsas, N; Berardelli, A; Pantano, P

2015-08-01

To evaluate gray matter (GM) and white matter (WM) abnormalities and their clinical correlates in patients with progressive supranuclear palsy (PSP). Sixteen PSP patients and sixteen age-matched healthy subjects underwent a clinical evaluation and multimodal magnetic resonance imaging, including three-dimensional T1-weighted imaging and diffusion tensor imaging (DTI). Volumetric and DTI analyses were computed using SPM and FSL tools. PSP patients showed GM volume decrease, involving the frontal cortex, putamen, pallidum, thalamus and accumbens nucleus, cerebellum, and brainstem. Additionally, they had widespread changes in WM bundles, mainly affecting cerebellar peduncles, thalamic radiations, corticospinal tracts, corpus callosum, and longitudinal fasciculi. GM volumes did not correlate with WM abnormalities. DTI indices of WM damage, but not GM volumes, correlated with clinical scores of disease severity and cognitive impairment. The neurodegenerative changes that occur in PSP involve both GM and WM structures and develop concurrently though independently. WM damage in PSP correlates with clinical scores of disease severity and cognitive impairment, thus providing further insight into the pathophysiology of the disease.

Nursing and the primacy of technological progress.

PubMed

Barnard, A

1999-12-01

This article identifies assumptions common to interpreting technological progress in contemporary nursing practice. Technology is described in terms of its characteristics and progress is identified as an ideological assumption influencing the way we think about, practice, and explain technology in contemporary nursing. Arguments associated with linear development, the elimination of scarcity, the technological imperative, the advancement of nursing, and technology as a neutral phenomenon are examined. It is argued that understanding progress assists us to develop insight into the relationship between technology and nursing.

Clinically Practical Approach for Screening of Low Muscularity Using Electronic Linear Measures on Computed Tomography Images in Critically Ill Patients.

PubMed

Avrutin, Egor; Moisey, Lesley L; Zhang, Roselyn; Khattab, Jenna; Todd, Emma; Premji, Tahira; Kozar, Rosemary; Heyland, Daren K; Mourtzakis, Marina

2017-12-06

Computed tomography (CT) scans performed during routine hospital care offer the opportunity to quantify skeletal muscle and predict mortality and morbidity in intensive care unit (ICU) patients. Existing methods of muscle cross-sectional area (CSA) quantification require specialized software, training, and time commitment that may not be feasible in a clinical setting. In this article, we explore a new screening method to identify patients with low muscle mass. We analyzed 145 scans of elderly ICU patients (≥65 years old) using a combination of measures obtained with a digital ruler, commonly found on hospital radiological software. The psoas and paraspinal muscle groups at the level of the third lumbar vertebra (L3) were evaluated by using 2 linear measures each and compared with an established method of CT image analysis of total muscle CSA in the L3 region. There was a strong association between linear measures of psoas and paraspinal muscle groups and total L3 muscle CSA (R 2 = 0.745, P < 0.001). Linear measures, age, and sex were included as covariates in a multiple logistic regression to predict those with low muscle mass; receiver operating characteristic (ROC) area under the curve (AUC) of the combined psoas and paraspinal linear index model was 0.920. Intraclass correlation coefficients (ICCs) were used to evaluate intrarater and interrater reliability, resulting in scores of 0.979 (95% CI: 0.940-0.992) and 0.937 (95% CI: 0.828-0.978), respectively. A digital ruler can reliably predict L3 muscle CSA, and these linear measures may be used to identify critically ill patients with low muscularity who are at risk for worse clinical outcomes. © 2017 American Society for Parenteral and Enteral Nutrition.

Changes in Clinical and Microbiological Periodontal Profiles Relate to Progression of Carotid Intima‐Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study

PubMed Central

Desvarieux, Moïse; Demmer, Ryan T.; Jacobs, David R.; Papapanou, Panos N.; Sacco, Ralph L.; Rundek, Tatjana

2013-01-01

Background No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. Methods and Results The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68±8 years old) and follow‐up. Over a 3‐year median follow‐up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA‐DNA checkerboard hybridization. Common carotid artery intima‐medial thickness (CCA‐IMT) was measured using high‐resolution ultrasound. In 2 separate analyses, change in periodontal status (follow‐up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥3‐mm probing depth (Δ%PD≥3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA‐IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Mean (SE) CCA‐IMT increased during follow‐up by 0.139±0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA‐IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD≥3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA‐IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance

Risk of Visual Field Progression in Glaucoma Patients with Progressive Retinal Nerve Fiber Layer Thinning: A 5-Year Prospective Study.

PubMed

Yu, Marco; Lin, Chen; Weinreb, Robert N; Lai, Gilda; Chiu, Vivian; Leung, Christopher Kai-Shun

2016-06-01

To investigate whether progressive retinal nerve fiber layer (RNFL) thinning is predictive of progressive visual field (VF) loss in glaucoma. Prospective study. A total of 139 primary open-angle glaucoma patients (240 eyes) followed up for ≥5 years. Retinal nerve fiber layer imaging and VF testing were performed at ∼4-month intervals. Progressive RNFL thinning was determined by event analysis (Guided Progression Analysis [GPA]) and trend analysis (Trend-based Progression Analysis [TPA]) of serial registered RNFL thickness maps. VF progression was detected according to the Early Manifest Glaucoma Trial (EMGT) ("likely progression") and pointwise linear regression (PLR) criteria (≥3 contiguous locations with sensitivity change <0 decibels [dB]/year at P < 0.01). Hazard ratios (HRs) for predicting VF progression were calculated by Cox proportional hazard modeling with progressive RNFL thinning as a time-dependent covariate. The specificity of GPA/TPA for detection of RNFL changes was determined by the proportion of eyes with significant RNFL thinning/thickening in 25 normal subjects followed weekly for 8 consecutive weeks and the proportion with significant RNFL thickening in the glaucoma group. The HRs of VF progression. A total of 65 (27.1%) and 117 eyes (48.8%) had progressive RNFL thinning based on GPA and TPA, respectively, and 30 (12.5%) and 39 eyes (16.3%) had VF progression per the EMGT and PLR criteria, respectively, during follow-up. Eyes with progressive RNFL thinning had lower VF survival estimates and a faster decline of visual field index than eyes without. Progressive RNFL thinning predicted the development of VF progression with HRs of 8.44 (95% confidence interval, 3.30-21.61) (EMGT criteria) and 5.11 (2.51-10.42) (PLR criteria) for TPA and 3.95 (1.74-8.93) (EMGT criteria) and 3.81 (1.83-7.92) (PLR criteria) for GPA after controlling for baseline covariates. The specificities of GPA and TPA were 100% (83.4%-100.0%) in the normal group and 81

Interventional multispectral photoacoustic imaging with a clinical linear array ultrasound probe for guiding nerve blocks

NASA Astrophysics Data System (ADS)

Xia, Wenfeng; West, Simeon J.; Nikitichev, Daniil I.; Ourselin, Sebastien; Beard, Paul C.; Desjardins, Adrien E.

2016-03-01

Accurate identification of tissue structures such as nerves and blood vessels is critically important for interventional procedures such as nerve blocks. Ultrasound imaging is widely used as a guidance modality to visualize anatomical structures in real-time. However, identification of nerves and small blood vessels can be very challenging, and accidental intra-neural or intra-vascular injections can result in significant complications. Multi-spectral photoacoustic imaging can provide high sensitivity and specificity for discriminating hemoglobin- and lipid-rich tissues. However, conventional surface-illumination-based photoacoustic systems suffer from limited sensitivity at large depths. In this study, for the first time, an interventional multispectral photoacoustic imaging (IMPA) system was used to image nerves in a swine model in vivo. Pulsed excitation light with wavelengths in the ranges of 750 - 900 nm and 1150 - 1300 nm was delivered inside the body through an optical fiber positioned within the cannula of an injection needle. Ultrasound waves were received at the tissue surface using a clinical linear array imaging probe. Co-registered B-mode ultrasound images were acquired using the same imaging probe. Nerve identification was performed using a combination of B-mode ultrasound imaging and electrical stimulation. Using a linear model, spectral-unmixing of the photoacoustic data was performed to provide image contrast for oxygenated and de-oxygenated hemoglobin, water and lipids. Good correspondence between a known nerve location and a lipid-rich region in the photoacoustic images was observed. The results indicate that IMPA is a promising modality for guiding nerve blocks and other interventional procedures. Challenges involved with clinical translation are discussed.

Clinical application of microencapsulated islets: actual prospectives on progress and challenges.

PubMed

Calafiore, Riccardo; Basta, Giuseppe

2014-04-01

After 25 years of intense pre-clinical work on microencapsulated intraperitoneal islet grafts into non-immunosuppressed diabetic recipients, the application of this procedure to patients with type 1 diabetes mellitus has been a significant step forward. This result, achieved in a few centers worldwide, underlies the safety of biopolymers used for microencapsulation. Without this advance, no permission for human application of microcapsules would have ever been obtained after years of purification technologies applied to the raw alginates. To improve safety of the encapsulated islet graft system, renewed efforts on the capsules' bioengineering, as well as on insulin-producing cells within the capsular membranes, are in progress. It is hoped that advances in these two critical aspects of the cell encapsulation technology will result in wider human application of this system. Copyright © 2013 Elsevier B.V. All rights reserved.

Neurofibrillary Tangle Stage and the Rate of Progression of Alzheimer Symptoms: Modeling Using an Autopsy Cohort and Application to Clinical Trial Design

PubMed Central

Qian, Jing; T.Hyman, Bradley; Betensky, Rebecca A.

2017-01-01

Importance The heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents. Objective To gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design. Design, Setting, and Participants A longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging’s Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria. Main Outcomes and Measures We sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years. We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity. Results Several correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = −0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P

Randomized Controlled Trial in Clinical Settings to Evaluate Effectiveness of Coping Skills Education Used with Progressive Tinnitus Management

ERIC Educational Resources Information Center

Henry, James A.; Thielman, Emily J.; Zaugg, Tara L.; Kaelin, Christine; Schmidt, Caroline J.; Griest, Susan; McMillan, Garnett P.; Myers, Paula; Rivera, Izel; Baldwin, Robert; Carlson, Kathleen

2017-01-01

Purpose: This randomized controlled trial evaluated, within clinical settings, the effectiveness of coping skills education that is provided with progressive tinnitus management (PTM). Method: At 2 Veterans Affairs medical centers, N = 300 veterans were randomized to either PTM intervention or 6-month wait-list control. The PTM intervention…

Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

PubMed

Wolk, David A; Sadowsky, Carl; Safirstein, Beth; Rinne, Juha O; Duara, Ranjan; Perry, Richard; Agronin, Marc; Gamez, Jose; Shi, Jiong; Ivanoiu, Adrian; Minthon, Lennart; Walker, Zuzana; Hasselbalch, Steen; Holmes, Clive; Sabbagh, Marwan; Albert, Marilyn; Fleisher, Adam; Loughlin, Paul; Triau, Eric; Frey, Kirk; Høgh, Peter; Bozoki, Andrea; Bullock, Roger; Salmon, Eric; Farrar, Gillian; Buckley, Christopher J; Zanette, Michelle; Sherwin, Paul F; Cherubini, Andrea; Inglis, Fraser

2018-05-14

Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were β-amyloid positive vs those who were β-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients

Thoracolumbar kyphosis in patients with mucopolysaccharidoses: clinical outcomes and predictive radiographic factors for progression of deformity.

PubMed

Roberts, S B; Dryden, R; Tsirikos, A I

2016-02-01

Clinical and radiological data were reviewed for all patients with mucopolysaccharidoses (MPS) with thoracolumbar kyphosis managed non-operatively or operatively in our institution. In all 16 patients were included (eight female: eight male; 50% male), of whom nine had Hurler, five Morquio and two Hunter syndrome. Six patients were treated non-operatively (mean age at presentation of 6.3 years; 0.4 to 12.9); mean kyphotic progression +1.5(o)/year; mean follow-up of 3.1 years (1 to 5.1) and ten patients operatively (mean age at presentation of 4.7 years; 0.9 to 14.4); mean kyphotic progression 10.8(o)/year; mean follow-up of 8.2 years; 4.8 to 11.8) by circumferential arthrodesis with posterior instrumentation in patients with flexible deformities (n = 6). In the surgical group (mean age at surgery of 6.6 years; 2.4 to 16.8); mean post-operative follow-up of 6.3 years (3.5 to 10.3), mean pre-operative thoracolumbar kyphosis of 74.3(o) (42(o) to 110(o)) was corrected to mean of 28.6(o) (0(o) to 65(o)) post-operatively, relating to a mean deformity correction of 66.9% (31% to 100%). Surgical complications included a deep wound infection treated by early debridement, apical non-union treated by posterior re-grafting, and stable adjacent segment spondylolisthesis managed non-operatively. Thoracolumbar kyphosis > +38(o) at initial presentation was identified as predicting progressively severe deformity with 90% sensitivity and 83% specificity. This study demonstrates that severe thoracolumbar kyphosis in patients with MPS can be effectively treated by circumferential arthrodesis. Severity of kyphosis at initial presentation may predict progression of thoracolumbar deformity. Patients with MPS may be particularly susceptible to post-operative complications due to the underlying connective tissue disorder and inherent immunological compromise. Clinical and radiological data were reviewed for all patients with mucopolysaccharidoses with thoracolumbar kyphosis managed non

Clinical Investigation Program Annual Progress Report.

DTIC Science & Technology

1983-09-30

Antiemetics (A Phase II Study).(O) ............... 049 79/110 Evaluation of Local Anesthetic Skin Testing and Progressive Challenge in Patients with a History ...Associated with Oat Cell Carcinoma. J Assoc Mil Derm 8, 1982. Grimwood, R.E.: The History and Principles of Immunofluorescence. J Assn Mil Derm 9(1...December, 1981. ""’ PRESENTATIONS: 1.) Kindig, N.B.: D CO correction using PaCO back pressure predicted from venous bloo . Sfresented: Carl E

A matched-pair comparison of inlay and onlay trochlear designs for patellofemoral arthroplasty: no differences in clinical outcome but less progression of osteoarthritis with inlay designs.

PubMed

Feucht, Matthias J; Cotic, Matthias; Beitzel, Knut; Baldini, Julia F; Meidinger, Gebhart; Schöttle, Philip B; Imhoff, Andreas B

2017-09-01

To compare clinical and radiographic results after isolated patellofemoral arthroplasty (PFA) using either a second-generation inlay or onlay trochlear design. The hypothesis was that an inlay design will produce better clinical results and less progression of tibiofemoral osteoarthritis (OA) compared to an onlay design. Fifteen consecutive patients undergoing isolated PFA with an onlay design trochlear component (Journey™ PFJ, Smith & Nephew) were matched with 15 patients after isolated PFA with an inlay design trochlear component (HemiCAP ® Wave, Arthrosurface). Matching criteria were age, gender, body mass index, and follow-up period. An independent observer evaluated patients prospectively, whereas data were compared retrospectively. Clinical outcome was assessed using WOMAC, Lysholm score, and pain VAS. Kellgren-Lawrence grading was used to assess progression of tibiofemoral OA. Conversion to total knee arthroplasty was necessary in one patient within each group, leaving 14 patients per group for final evaluation. The mean follow-up was 26 months in the inlay group and 25 months in the onlay group (n.s.). Both groups displayed significant improvements of all clinical scores (p < 0.05). No significant differences were found between the two groups with regard to the clinical outcome and reoperation rate. No significant progression of tibiofemoral OA was observed in the inlay group, whereas 53 % of the onlay group showed progression of medial and/or lateral tibiofemoral OA (p = 0.009). Isolated PFA using either a second-generation inlay or onlay trochlear component significantly improves functional outcome scores and pain. The theoretical advantages of an inlay design did not result in better clinical outcome scores; however, progression of tibiofemoral OA was significantly less common in patients with an inlay trochlear component. This implant design may therefore improve long-term results and survival rates after isolated PFA. III.

Commensurate Priors for Incorporating Historical Information in Clinical Trials Using General and Generalized Linear Models

PubMed Central

Hobbs, Brian P.; Sargent, Daniel J.; Carlin, Bradley P.

2014-01-01

Assessing between-study variability in the context of conventional random-effects meta-analysis is notoriously difficult when incorporating data from only a small number of historical studies. In order to borrow strength, historical and current data are often assumed to be fully homogeneous, but this can have drastic consequences for power and Type I error if the historical information is biased. In this paper, we propose empirical and fully Bayesian modifications of the commensurate prior model (Hobbs et al., 2011) extending Pocock (1976), and evaluate their frequentist and Bayesian properties for incorporating patient-level historical data using general and generalized linear mixed regression models. Our proposed commensurate prior models lead to preposterior admissible estimators that facilitate alternative bias-variance trade-offs than those offered by pre-existing methodologies for incorporating historical data from a small number of historical studies. We also provide a sample analysis of a colon cancer trial comparing time-to-disease progression using a Weibull regression model. PMID:24795786

Refining a learning progression of energy

NASA Astrophysics Data System (ADS)

Yao, Jian-Xin; Guo, Yu-Ying; Neumann, Knut

2017-11-01

This paper presents a revised learning progression for the energy concept and initial findings on diverse progressions among subgroups of sample students. The revised learning progression describes how students progress towards an understanding of the energy concept along two progress variables identified from previous studies - key ideas about energy and levels of conceptual development. To assess students understanding with respect to the revised learning progression, we created a specific instrument, the Energy Concept Progression Assessment (ECPA) based on previous work on assessing students' understanding of energy. After iteratively refining the instrument in two pilot studies, the ECPA was administered to a total of 4550 students (Grades 8-12) from schools in two districts in a major city in Mainland China. Rasch analysis was used to examine the validity of the revised learning progression and explore factors explaining different progressions. Our results confirm the validity of the four conceptual development levels. In addition, we found that although following a similar progression pattern, students' progression rate was significantly influenced by environmental factors such as school type. In the discussion of our findings, we address the non-linear and complex nature of students' progression in understanding energy. We conclude with illuminating our research's implication for curriculum design and energy teaching.

Curriculum-Based Measurement of Oral Reading: Quality of Progress Monitoring Outcomes

ERIC Educational Resources Information Center

Christ, Theodore J.; Zopluoglu, Cengiz; Long, Jeffery D.; Monaghen, Barbara D.

2012-01-01

Curriculum-based measurement of oral reading (CBM-R) is frequently used to set student goals and monitor student progress. This study examined the quality of growth estimates derived from CBM-R progress monitoring data. The authors used a linear mixed effects regression (LMER) model to simulate progress monitoring data for multiple levels of…

Progressive nonfluent aphasia: a rare clinical subtype of FTLD-TDP in Japan.

PubMed

Aoki, Naoya; Tsuchiya, Kuniaki; Kobayashi, Zen; Arai, Tetsuaki; Togo, Takashi; Miyazaki, Hiroshi; Kondo, Hiromi; Ishizu, Hideki; Uchikado, Hirotake; Katsuse, Omi; Hirayasu, Yoshio; Akiyama, Haruhiko

2012-06-01

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD-tau) and FTLD with TDP-43 accumulation (FTLD-TDP) both cause PNFA. We reviewed clinical records of 29 FTLD-TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81-year-old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP-43-immunoreactive neuronal cytoplasmic inclusions and round or irregular-shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD-TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries. © 2011 Japanese Society of Neuropathology.

New clinical trial to study long-term progression of brain and spine cancers | Center for Cancer Research

Cancer.gov

Dr. Mark Gilbert, Chief, Neuro-Oncology Branch, describes an ambitious new clinical trial that, for the first time, will study the long-term progression of brain and spine cancers. The 10,000 patient trial is the largest of its kind and will follow patients throughout the course of their disease. In addition to identifying optimal treatments for common brain and spine cancers,

Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials

PubMed Central

van Eijk, Ruben P A; Eijkemans, Marinus J C; Ferguson, Toby A; Nikolakopoulos, Stavros; Veldink, Jan H; van den Berg, Leonard H

2018-01-01

Objectives Plasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials. Methods We used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power. Results A total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size. Conclusions Plasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome. PMID:29084868

Attitudes of clinical faculty about career progress, career success and recognition, and commitment to academic medicine. Results of a survey.

PubMed

Buckley, L M; Sanders, K; Shih, M; Hampton, C L

2000-09-25

To assess attitudes about career progress, resources for career development, and commitment to academic medicine in physician faculty at an academic medical center who spend more than 50% of their time in clinical care. Faculty survey. Academic medical center and associated Veterans Affairs medical center. A total of 310 physician faculty responded to the survey. Half of the faculty reported spending 50% or less of their time in clinical care (mean, 31% of time) (group 1) and half reported spending more than 50% of their time in clinical care (mean, 72% of time) (group 2). Group 2 faculty had one third of the time for scholarly activities, reported slower career progress, and were less likely to be at the rank of professor (40% and 16% for groups 1 and 2, respectively; P<.001) or to be tenured (52% and 26%, respectively; P<.001) despite similar age and years on faculty. Group 2 faculty were 50% more likely to report that tenure and promotion criteria were not reviewed at their annual progress report (P =.003) and that they did not understand the criteria (P<.001). Group 2 faculty valued excellence in patient care over scholarship and national visibility. Group 2 faculty reported greater dissatisfaction with academic medicine and less commitment to a career in academic medicine. Physician faculty who spend more than 50% of their time in clinical care have less time, mentoring, and resources needed for development of an academic career. These obstacles plus differences in their attitudes about career success and recognition contribute to significant differences in promotion. These factors are associated with greater dissatisfaction with academic medicine and lower commitment to academic careers.

Progressively Worsening Premature Coronary Artery Disease: Adding Anticoagulation Stabilizes-Reverses Clinical Symptomatic Disease Progression in Thrombophilic-Atherothrombotic Patients: A Pilot Study.

PubMed

Rothschild, Matan; Jetty, Vybhav; Mahida, Christopher; Wang, Ping; Prince, Marloe; Goldenberg, Naila; Glueck, Charles J

2017-11-01

In 35 patients with 116 severe premature cardiovascular disease (CVD) events (median age: 48 years), 14 having worsening CVD despite maximal intervention, we evaluated thrombophilia and speculated that anticoagulation might arrest-reverse progressive thrombophilic-atherothrombotic CVD. Thrombophilia-hypofibrinolysis in the 35 patients was compared to 110 patients with venous thromboembolism (VTE) without CVD and to 110 healthy normal controls. Efficacy-safety of anticoagulation was prospectively assessed in 14 of the 35 patients whose CVD worsened over 2 years despite maximal medical-surgical intervention. At entry on maximally tolerated lipid-lowering therapy, median low-density lipoprotein was 88 mg/dL. Measures of thrombophilia-hypofibrinolysis in the 35 cases differed from 110 VTE controls only for the lupus anticoagulant, present in 6 (21%) of 28 cases versus 4 (4%) of 91 VTE controls ( P = .01), and for high anticardiolipin antibodies (ACLAs) immunoglobulin G, 5 (14%) of 35 cases versus 4 of 108 VTE controls (4%), P = .04. The 14 patients who were anticoagulated differed from 110 VTE controls only for the lupus anticoagulant, 38% versus 4%, P = .001, and for high lipoprotein (a), 46% versus 17%, P = .028, respectively. The 14 patients with atherothrombosis having inexorably worsening CAD despite maximal medical-surgical therapy were anticoagulated for 6.5 years (median), with clinical CVD progression arrested in 12 (86%), and all 12 became asymptomatic. In the 35 patients with premature CVD, thrombophilia was pervasive, comparable to or more severe than in VTE controls without CVD. When CVD progressively worsens despite maximal intervention, thrombophilia and atherosclerosis (atherothrombosis) are commonly concurrent, and the downhill course of CVD may be arrested-stabilized by anticoagulation.

Frequency of Testing to Detect Visual Field Progression Derived Using a Longitudinal Cohort of Glaucoma Patients.

PubMed

Wu, Zhichao; Saunders, Luke J; Daga, Fábio B; Diniz-Filho, Alberto; Medeiros, Felipe A

2017-06-01

To determine the time required to detect statistically significant progression for different rates of visual field loss using standard automated perimetry (SAP) when considering different frequencies of testing using a follow-up scheme that resembles clinical practice. Observational cohort study. One thousand seventy-two eyes of 665 patients with glaucoma followed up over an average of 4.3±0.9 years. Participants with 5 or more visual field tests over a 2- to 5-year period were included to derive the longitudinal measurement variability of SAP mean deviation (MD) using linear regressions. Estimates of variability then were used to reconstruct real-world visual field data by computer simulation to evaluate the time required to detect progression for various rates of visual field loss and different frequencies of testing. The evaluation was performed using a follow-up scheme that resembled clinical practice by requiring a set of 2 baseline tests and a confirmatory test to identify progression. Time (in years) required to detect progression. The time required to detect a statistically significant negative MD slope decreased as the frequency of testing increased, albeit not proportionally. For example, 80% of eyes with an MD loss of -2 dB/year would be detected after 3.3, 2.4, and 2.1 years when testing is performed once, twice, and thrice per year, respectively. For eyes with an MD loss of -0.5 dB/year, progression can be detected with 80% power after 7.3, 5.7, and 5.0 years, respectively. This study provides information on the time required to detect progression using MD trend analysis in glaucoma eyes when different testing frequencies are used. The smaller gains in the time to detect progression when testing is increased from twice to thrice per year suggests that obtaining 2 reliable tests at baseline followed by semiannual testing and confirmation of progression through repeat testing in the initial years of follow-up may provide a good compromise for

Progress Report on the Improved Linear Ion Trap Physics Package

NASA Technical Reports Server (NTRS)

Prestage, John D.

1995-01-01

This article describes the first operational results from the extended linear ion trap frequency standard now being developed at JPL. This new design separates the state selection/interrogation region from the more critical microwave resonance region where the multiplied local oscillator (LO) signal is compared to the stable atomic transition. Hg+ ions have been trapped, shuttled back and forth between the resonance and state selection traps. In addition, microwave transitions between the Hg+ clock levels have been driven in the resonance trap and detected in the state selection trap.

Levels of uninvolved immunoglobulins predict clinical status and progression-free survival for multiple myeloma patients.

PubMed

Harutyunyan, Nika M; Vardanyan, Suzie; Ghermezi, Michael; Gottlieb, Jillian; Berenson, Ariana; Andreu-Vieyra, Claudia; Berenson, James R

2016-07-01

Multiple myeloma (MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite (HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma. © 2016 John Wiley & Sons Ltd.

Evaluation of Glaucoma Progression in Large-Scale Clinical Data: The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG).

PubMed

Fujino, Yuri; Asaoka, Ryo; Murata, Hiroshi; Miki, Atsuya; Tanito, Masaki; Mizoue, Shiro; Mori, Kazuhiko; Suzuki, Katsuyoshi; Yamashita, Takehiro; Kashiwagi, Kenji; Shoji, Nobuyuki

2016-04-01

To develop a large-scale real clinical database of glaucoma (Japanese Archive of Multicentral Databases in Glaucoma: JAMDIG) and to investigate the effect of treatment. The study included a total of 1348 eyes of 805 primary open-angle glaucoma patients with 10 visual fields (VFs) measured with 24-2 or 30-2 Humphrey Field Analyzer (HFA) and intraocular pressure (IOP) records in 10 institutes in Japan. Those with 10 reliable VFs were further identified (638 eyes of 417 patients). Mean total deviation (mTD) of the 52 test points in the 24-2 HFA VF was calculated, and the relationship between mTD progression rate and seven variables (age, mTD of baseline VF, average IOP, standard deviation (SD) of IOP, previous argon/selective laser trabeculoplasties (ALT/SLT), previous trabeculectomy, and previous trabeculotomy) was analyzed. The mTD in the initial VF was -6.9 ± 6.2 dB and the mTD progression rate was -0.26 ± 0.46 dB/year. Mean IOP during the follow-up period was 13.5 ± 2.2 mm Hg. Age and SD of IOP were related to mTD progression rate. However, in eyes with average IOP below 15 and also 13 mm Hg, only age and baseline VF mTD were related to mTD progression rate. Age and the degree of VF damage were related to future progression. Average IOP was not related to the progression rate; however, fluctuation of IOP was associated with faster progression, although this was not the case when average IOP was below 15 mm Hg.

Robust Classification and Segmentation of Planar and Linear Features for Construction Site Progress Monitoring and Structural Dimension Compliance Control

NASA Astrophysics Data System (ADS)

Maalek, R.; Lichti, D. D.; Ruwanpura, J.

2015-08-01

The application of terrestrial laser scanners (TLSs) on construction sites for automating construction progress monitoring and controlling structural dimension compliance is growing markedly. However, current research in construction management relies on the planned building information model (BIM) to assign the accumulated point clouds to their corresponding structural elements, which may not be reliable in cases where the dimensions of the as-built structure differ from those of the planned model and/or the planned model is not available with sufficient detail. In addition outliers exist in construction site datasets due to data artefacts caused by moving objects, occlusions and dust. In order to overcome the aforementioned limitations, a novel method for robust classification and segmentation of planar and linear features is proposed to reduce the effects of outliers present in the LiDAR data collected from construction sites. First, coplanar and collinear points are classified through a robust principal components analysis procedure. The classified points are then grouped using a robust clustering method. A method is also proposed to robustly extract the points belonging to the flat-slab floors and/or ceilings without performing the aforementioned stages in order to preserve computational efficiency. The applicability of the proposed method is investigated in two scenarios, namely, a laboratory with 30 million points and an actual construction site with over 150 million points. The results obtained by the two experiments validate the suitability of the proposed method for robust segmentation of planar and linear features in contaminated datasets, such as those collected from construction sites.

Corpus callosum damage predicts disability progression and cognitive dysfunction in primary-progressive MS after five years.

PubMed

Bodini, Benedetta; Cercignani, Mara; Khaleeli, Zhaleh; Miller, David H; Ron, Maria; Penny, Sophie; Thompson, Alan J; Ciccarelli, Olga

2013-05-01

We aim to identify specific areas of white matter (WM) and grey matter (GM), which predict disability progression and cognitive dysfunction after five years in patients with primary-progressive multiple sclerosis (PPMS). Thirty-two patients with early PPMS were assessed at baseline and after five years on the Expanded Disability Status Scale (EDSS), and EDSS step-changes were calculated. At year five, a subgroup of 25 patients and 31 healthy controls underwent a neuropsychological assessment. Baseline imaging consisted of dual-echo (proton density and T2-weighted), T1-weighted volumetric, and diffusion tensor imaging. Fractional anisotropy (FA) maps were created, and fed into tract-based spatial statistics. To compensate for the potential bias introduced by WM lesions, the T1 volumes underwent a lesion-filling procedure before entering a voxel-based morphometry protocol. To investigate whether FA and GM volume predicted EDSS step-changes over five years and neuropsychological tests scores at five years, voxelwise linear regression analyses were performed. Lower FA in the splenium of the corpus callosum (CC) predicted a greater progression of disability over the follow-up. Lower FA along the entire CC predicted worse verbal memory, attention and speed of information processing, and executive function at five years. GM baseline volume did not predict any clinical variable. Our findings highlight the importance of damage to the interhemispheric callosal pathways in determining physical and cognitive disability in PPMS. Disruption of these pathways, which interconnect motor and cognitive networks between the two hemispheres, may result in a disconnection syndrome that contributes to long-term physical and cognitive disability. Copyright © 2011 Wiley Periodicals, Inc.

Linear IgA bullous dermatosis in a neonate.

PubMed

Hruza, L L; Mallory, S B; Fitzgibbons, J; Mallory, G B

1993-06-01

A newborn black boy had two facial blisters at birth that progressed to bullous lesions over the trunk, genitals, extremities, and oral and tracheal mucosa. A biopsy specimen demonstrated a subepidermal bulla with mixed eosinophilic and neutrophilic, inflammatory infiltrate. Direct immunofluorescence showed linear IgA, IgG, and C3 depositions along the basement membrane zone, consistent with a diagnosis of childhood linear IgA bullous dermatosis (chronic bullous dermatosis of childhood). The skin disease was controlled with combined prednisone and dapsone. This is the youngest reported patient with the disease. Linear IgA bullous dermatosis should be considered in the differential diagnosis of blistering diseases of the newborn, and immunofluorescence should be performed on a skin biopsy specimen.

[Research progress in mechanisms and clinical application for blonanserin and lurasidone in improving cognitive function of schizophrenia].

PubMed

Zheng, Qi; Liu, Bangshan; Xu, Shuyin; Liao, Mei; Zhang, Yan; Li, Lingjiang

2017-04-28

Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials.

PubMed

Weiner, Michael W; Veitch, Dallas P; Aisen, Paul S; Beckett, Laurel A; Cairns, Nigel J; Green, Robert C; Harvey, Danielle; Jack, Clifford R; Jagust, William; Morris, John C; Petersen, Ronald C; Saykin, Andrew J; Shaw, Leslie M; Toga, Arthur W; Trojanowski, John Q

2017-04-01

The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. We used standard searches to find publications using ADNI data. (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and

From linear to nonlinear control means: a practical progression.

PubMed

Gao, Zhiqiang

2002-04-01

With the rapid advance of digital control hardware, it is time to take the simple but effective proportional-integral-derivative (PID) control technology to the next level of performance and robustness. For this purpose, a nonlinear PID and active disturbance rejection framework are introduced in this paper. It complements the existing theory in that (1) it actively and systematically explores the use of nonlinear control mechanisms for better performance, even for linear plants; (2) it represents a control strategy that is rather independent of mathematical models of the plants, thus achieving inherent robustness and reducing design complexity. Stability analysis, as well as software/hardware test results, are presented. It is evident that the proposed framework lends itself well in seeking innovative solutions to practical problems while maintaining the simplicity and the intuitiveness of the existing technology.

Association between haptoglobin and IgM levels and the clinical progression of caseous lymphadenitis in sheep

PubMed Central

2013-01-01

Background Sheep caseous lymphadenitis (CLA), caused by Corynebacterium pseudotuberculosis (Cp), is associated with direct economic losses and presents significant zoonotic potential. Despite the importance of the disease, a satisfactory vaccine model has not been developed. Thus, this study aimed to investigate the association between haptoglobin (Hp) and IgM levels and the clinical progression of CLA in primarily infected sheep and in sheep immunized with Cp- secreted antigens adjuvanted with Quillaja saponaria saponins. These animals were kept with CLA-positive sheep to simulate natural exposure that occurs in field conditions. During the experiment, the Hp and IgM levels were monitored for 21 days, and the development of internal CLA lesions was investigated through necropsies on day182 post-immunization. Results Primarily infected sheep in Group 2 (inoculated with 2x105 Cp virulent strain) had higher Hp values between the first and ninth days post inoculation (PI) than sheep in Group 1 (control; P < 0.05). Immunized animals in Group 3 had significantly higher Hp values between the third and seventh days PI, compared with the control group (P < 0.01). Binary logistic regression (BLR) analysis of primarily infected sheep indicated an association between Hp concentration and CLA clinical progression: animals with high Hp values had 99.9% less risk of having CLA abscesses than animals with low Hp levels (Odds ratio = 0.001, P < 0.05). Both experimental groups had significantly higher IgM titers than the control group around the ninth and eleventh days PI (P < 0.05). The BLR analysis for immunized sheep indicated an association between IgM levels and clinical progression: sheep with high IgM titers had 100.0% less risk of having CLA abscesses than animals with low IgM levels (Odds ratio = 0.000, P < 0.05). Conclusions Resistance to C. pseudotuberculosis infection is supported by the early acute phase response, in which up-regulation of

Overview of NASA Magnet and Linear Alternator Research Efforts

NASA Astrophysics Data System (ADS)

Geng, Steven M.; Niedra, Janis M.; Schwarze, Gene E.

2005-02-01

The Department of Energy, Lockheed Martin, Stirling Technology Company, and NASA Glenn Research Center are developing a high-efficiency, 110 watt Stirling Radioisotope Generator (SRG110) for NASA Space Science missions. NASA Glenn is conducting in-house research on rare earth permanent magnets and on linear alternators to assist in developing a free-piston Stirling convertor for the SRG110 and for developing advanced technology. The permanent magnet research efforts include magnet characterization, short-term magnet aging tests, and long-term magnet aging tests. Linear alternator research efforts have begun just recently at GRC with the characterization of a moving iron type linear alternator using GRC's alternator test rig. This paper reports on the progress and future plans of GRC's magnet and linear alternator research efforts.

Overview of NASA Magnet and Linear Alternator Research Efforts

NASA Technical Reports Server (NTRS)

Geng, Steven M.; Schwarze, Gene E.; Nieda, Janis M.

2005-01-01

The Department of Energy, Lockheed Martin, Stirling Technology Company, and NASA Glenn Research Center are developing a high-efficiency, 110 watt Stirling Radioisotope Generator (SRG110) for NASA Space Science missions. NASA Glenn is conducting in-house research on rare earth permanent magnets and on linear alternators to assist in developing a free-piston Stirling convertor for the SRG110 and for developing advanced technology. The permanent magnet research efforts include magnet characterization, short-term magnet aging tests, and long-term magnet aging tests. Linear alternator research efforts have begun just recently at GRC with the characterization of a moving iron type linear alternator using GRC's alternator test rig. This paper reports on the progress and future plans of GRC's magnet and linear alternator research efforts.

Progressive Visual Analytics: User-Driven Visual Exploration of In-Progress Analytics.

PubMed

Stolper, Charles D; Perer, Adam; Gotz, David

2014-12-01

As datasets grow and analytic algorithms become more complex, the typical workflow of analysts launching an analytic, waiting for it to complete, inspecting the results, and then re-Iaunching the computation with adjusted parameters is not realistic for many real-world tasks. This paper presents an alternative workflow, progressive visual analytics, which enables an analyst to inspect partial results of an algorithm as they become available and interact with the algorithm to prioritize subspaces of interest. Progressive visual analytics depends on adapting analytical algorithms to produce meaningful partial results and enable analyst intervention without sacrificing computational speed. The paradigm also depends on adapting information visualization techniques to incorporate the constantly refining results without overwhelming analysts and provide interactions to support an analyst directing the analytic. The contributions of this paper include: a description of the progressive visual analytics paradigm; design goals for both the algorithms and visualizations in progressive visual analytics systems; an example progressive visual analytics system (Progressive Insights) for analyzing common patterns in a collection of event sequences; and an evaluation of Progressive Insights and the progressive visual analytics paradigm by clinical researchers analyzing electronic medical records.

[Clinical risk factors for progressive myopia].

PubMed

Schaeffel, F

2012-08-01

The average worldwide frequency of myopia is approximately 30 % and is traditionally subdivided into school myopia and pathological myopia. A further distinction is made between progressive myopia and stationary myopia. There is a high correlation between the frequency of myopia and urbanization and training. Risk factors for development of myopia are close-up work, lack of outdoor activity, biometrical variables of the eye and genetic risk factors. Development of myopia can be positively influenced by peripheral focusing, increased exposure to light and in the future possibly pharmacologically.

Photorefractive keratectomy (PRK) at 193 nm using an erodible mask: new developments and clinical progress

NASA Astrophysics Data System (ADS)

Gordon, Michael; Seiler, Theo; Carey, Joseph P.; Friedman, Marc D.; Johnsson, N. M. F.; King, Michael C.; Muller, David F.

1993-06-01

This paper reports on our progress using an erodible mask to perform photorefractive keratectomy (PRK) for the correction of myopic astigmatism. We describe modifications to the mask, the mask eye cup and the surgical microscope aimed at simplifying the procedure and improving the ergonomics of the hardware. We report the clinical results of the post-op exam for 20 patients who have undergone PRK for myopic astigmatism under a Phase IIA study. The results compare favorably with an earlier Phase IIA study for performing PRK with a computer-controlled iris. Most important, the clinical data show the absence of any significant corneal haze and no significant decrease in spectacle corrected visual acuity. Although more long term follow-up is needed, the preliminary results support the safety and effectiveness of using an erodible mask to perform PRK for myopic astigmatism.

Discordance between 'actual' and 'scheduled' check-in times at a heart failure clinic.

PubMed

Gorodeski, Eiran Z; Joyce, Emer; Gandesbery, Benjamin T; Blackstone, Eugene H; Taylor, David O; Tang, W H Wilson; Starling, Randall C; Hachamovitch, Rory

2017-01-01

A 2015 Institute Of Medicine statement "Transforming Health Care Scheduling and Access: Getting to Now", has increased concerns regarding patient wait times. Although waiting times have been widely studied, little attention has been paid to the role of patient arrival times as a component of this phenomenon. To this end, we investigated patterns of patient arrival at scheduled ambulatory heart failure (HF) clinic appointments and studied its predictors. We hypothesized that patients are more likely to arrive later than scheduled, with progressively later arrivals later in the day. Using a business intelligence database we identified 6,194 unique patients that visited the Cleveland Clinic Main Campus HF clinic between January, 2015 and January, 2017. This clinic served both as a tertiary referral center and a community HF clinic. Transplant and left ventricular assist device (LVAD) visits were excluded. Punctuality was defined as the difference between 'actual' and 'scheduled' check-in times, whereby negative values (i.e., early punctuality) were patients who checked-in early. Contrary to our hypothesis, we found that patients checked-in late only a minority of the time (38% of visits). Additionally, examining punctuality by appointment hour slot we found that patients scheduled after 8AM had progressively earlier check-in times as the day progressed (P < .001 for trend). In both a Random Forest-Regression framework and linear regression models the most important risk-adjusted predictors of early punctuality were: later in the day appointment hour slot, patient having previously been to the hospital, age in the early 70s, and white race. Patients attending a mixed population ambulatory HF clinic check-in earlier than scheduled times, with progressive discrepant intervals throughout the day. This finding may have significant implications for provider utilization and resource planning in order to maximize clinic efficiency. The impact of elective early arrival on

The Economic and Clinical Impact of Sustained Use of a Progressive Mobility Program in a Neuro-ICU.

PubMed

Hester, Jeannette M; Guin, Peggy R; Danek, Gale D; Thomas, Jaime R; Titsworth, William L; Reed, Richard K; Vasilopoulos, Terrie; Fahy, Brenda G

2017-06-01

To investigate a progressive mobility program in a neurocritical care population with the hypothesis that the benefits and outcomes of the program (e.g., decreased length of stay) would have a significant positive economic impact. Retrospective analysis of economic and clinical outcome data before, immediately following, and 2 years after implementation of the Progressive Upright Mobility Protocol Plus program (UF Health Shands Hospital, Gainesville, FL) involving a series of planned movements in a sequential manner with an additional six levels of rehabilitation in the neuro-ICU at UF Health Shands Hospital. Thirty-bed neuro-ICU in an academic medical center. Adult neurologic and neurosurgical patients: 1,118 patients in the pre period, 731 patients in the post period, and 796 patients in the sustained period. Implementation of Progressive Upright Mobility Protocol Plus. ICU length of stay decreased from 6.5 to 5.8 days in the immediate post period and 5.9 days in the sustained period (F(2,2641) = 3.1; p = 0.045). Hospital length of stay was reduced from 11.3 ± 14.1 days to 8.6 ± 8.8 post days and 8.8 ± 9.3 days sustained (F(2,2641) = 13.0; p < 0.001). The impact of the study intervention on ICU length of stay (p = 0.031) and hospital length of stay (p < 0.001) remained after adjustment for age, sex, diagnoses, sedation, and ventilation. Hospital-acquired infections were reduced by 50%. Average total cost per patient after adjusting for inflation was significantly reduced by 16% (post period) and 11% (sustained period) when compared with preintervention (F(2,2641) = 3.1; p = 0.045). Overall, these differences translated to an approximately $12.0 million reduction in direct costs from February 2011 through the end of 2013. An ongoing progressive mobility program in the neurocritical care population has clinical and financial benefits associated with its implementation and should be considered.

Progress and challenges in TB vaccine development

PubMed Central

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H.E.; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development. PMID:29568497

Progress and challenges in TB vaccine development.

PubMed

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H E; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

PubMed Central

Ye, Byong Duk; McGovern, Dermot P.B.

2016-01-01

Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD. PMID:27156530

Primary Progressive Aphasia

MedlinePlus

... condition has three types, which cause different symptoms. Semantic variant primary progressive aphasia Symptoms include these difficulties: ... a not-for-profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does ...

Advanced statistics: linear regression, part II: multiple linear regression.

PubMed

Marill, Keith A

2004-01-01

The applications of simple linear regression in medical research are limited, because in most situations, there are multiple relevant predictor variables. Univariate statistical techniques such as simple linear regression use a single predictor variable, and they often may be mathematically correct but clinically misleading. Multiple linear regression is a mathematical technique used to model the relationship between multiple independent predictor variables and a single dependent outcome variable. It is used in medical research to model observational data, as well as in diagnostic and therapeutic studies in which the outcome is dependent on more than one factor. Although the technique generally is limited to data that can be expressed with a linear function, it benefits from a well-developed mathematical framework that yields unique solutions and exact confidence intervals for regression coefficients. Building on Part I of this series, this article acquaints the reader with some of the important concepts in multiple regression analysis. These include multicollinearity, interaction effects, and an expansion of the discussion of inference testing, leverage, and variable transformations to multivariate models. Examples from the first article in this series are expanded on using a primarily graphic, rather than mathematical, approach. The importance of the relationships among the predictor variables and the dependence of the multivariate model coefficients on the choice of these variables are stressed. Finally, concepts in regression model building are discussed.

LCFIPlus: A framework for jet analysis in linear collider studies

NASA Astrophysics Data System (ADS)

Suehara, Taikan; Tanabe, Tomohiko

2016-02-01

We report on the progress in flavor identification tools developed for a future e+e- linear collider such as the International Linear Collider (ILC) and Compact Linear Collider (CLIC). Building on the work carried out by the LCFIVertex collaboration, we employ new strategies in vertex finding and jet finding, and introduce new discriminating variables for jet flavor identification. We present the performance of the new algorithms in the conditions simulated using a detector concept designed for the ILC. The algorithms have been successfully used in ILC physics simulation studies, such as those presented in the ILC Technical Design Report.

Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis.

PubMed

Nam, Jackie L; Hensor, Elizabeth M A; Hunt, Laura; Conaghan, Philip G; Wakefield, Richard J; Emery, Paul

2016-12-01

To determine whether ultrasound can identify anti-cyclic citrullinated peptide (anti-CCP) antibody-positive patients without clinical synovitis (CS) who progress to inflammatory arthritis (IA). In a prospective study, anti-CCP-positive patients without CS underwent ultrasound imaging of 32 joints (wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints (MTPs)) and were monitored for the development of IA. Associations between baseline ultrasound findings (grey scale (GS), power Doppler (PD) and erosions) and (1) progression to IA and (2) development of CS within an individual joint were measured. Consecutive anti-CCP-positive patients (n=136; mean age 51 years, 100 women) were followed up for median of 18.3 months (range 0.1-79.6). At baseline 96% had GS, 30% had PD and 21% had one or more erosions. IA developed in 57 patients (42%) after median of 8.6 months (range 0.1-52.4). Ultrasound abnormalities (GS ≥2, PD ≥1 or erosion ≥1) were found in 86% at baseline compared with 67% of non-progressors (χ 2 =6.3, p=0.012). Progression to IA was significantly higher in those with ultrasound findings in any joint (excluding MTPs for GS) (GS ≥2: 55% vs 24%, HR (95% CI) 2.3 (1.0 to 4.9), p=0.038; PD ≥2: 75% vs 32%, 3.7 (2.0 to 6.9), p<0.001 and erosion ≥1: 71% vs 34%, 2.9 (1.7 to 5.1), p<0.001). Furthermore, progression occurred earlier with PD ≥2 (median 7.1 vs 52.4 months) and erosion ≥1 (15.4 vs 46.5). At the individual joint level, the trend for progression to CS was more significant for GS and PD (GS ≥2: 26% vs 3%, 9.4 (5.1 to 17.5), p<0.001; PD ≥2: 55% vs 4%, 31.3 (15.6 to 62.9), p<0.001). Ultrasound features of joint inflammation may be detected in anti-CCP-positive patients without CS. Ultrasound findings predict progression (and rate of progression) to IA, with the risk of progression highest in those with PD signal. NCT02012764; Results. Published by the BMJ Publishing Group Limited. For

Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

PubMed Central

Brettschneider, Johannes; Toledo, Jon B.; Van Deerlin, Vivianna M.; Elman, Lauren; McCluskey, Leo; Lee, Virginia M.-Y.; Trojanowski, John Q.

2012-01-01

Background/Aims We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits. PMID:22720079

Patellofemoral Osteoarthritis Progression and Alignment Changes after Open-Wedge High Tibial Osteotomy Do Not Affect Clinical Outcomes at Mid-term Follow-up.

PubMed

Goshima, Kenichi; Sawaguchi, Takeshi; Shigemoto, Kenji; Iwai, Shintaro; Nakanishi, Akira; Ueoka, Ken

2017-10-01

To evaluate the clinical and radiological outcomes of open-wedge high tibial osteotomy (OWHTO) with respect to the patellofemoral joint and to assess whether patellofemoral osteoarthritis (OA) progression and alignment changes after OWHTO affect clinical outcomes. Inclusion criteria were consecutive patients who underwent OWHTO from March 2005 to September 2013. Exclusion criteria were loss to follow-up within 2 years and absence of second-look arthroscopy findings at the time of plate removal. The clinical parameters, including anterior knee pain while climbing stairs, Japanese Orthopedic Association score, and Oxford Knee Score, were evaluated. Radiological outcomes, including weight-bearing line ratio, modified Blackburne-Peel ratio, posterior tibial slope, tilting angle, lateral shift ratio, and patellofemoral OA (Kellgren-Lawrence grade), were evaluated preoperatively and at the final follow-up. Cartilage status (International Cartilage Repair Society grade) was evaluated at the initial HTO and at plate removal. Fifty-three patients (60 knees) were included in this study. The mean follow-up was 58.2 ± 22.4 months. Two knees (3%) presented with mild anterior knee pain after OWHTO. The mean Japanese Orthopedic Association score (66.9 ± 11.2 to 91.2 ± 9.7) significantly improved (P < .001), and the mean Oxford Knee Score at the final follow-up was 42.0 ± 5.3. The mean modified Blackburne-Peel ratio (0.9 ± 0.1 to 0.7 ± 0.1, P < .001) and tilting angle (6.8 ± 3.7 to 5.6 ± 3.4, P = .033) significantly decreased after OWHTO, whereas no significant changes in posterior tibial slope (P = .511) and lateral shift ratio (P = .522) were observed. Radiologically, patellofemoral OA had progressed in 15 knees (27%), and arthroscopically patellofemoral cartilage degeneration had progressed in 27 knees (45%). However, there was no significant correlation between changes in patellofemoral alignment and clinical outcomes. Changes in patellofemoral alignment and

Interior-Point Methods for Linear Programming: A Review

ERIC Educational Resources Information Center

Singh, J. N.; Singh, D.

2002-01-01

The paper reviews some recent advances in interior-point methods for linear programming and indicates directions in which future progress can be made. Most of the interior-point methods belong to any of three categories: affine-scaling methods, potential reduction methods and central path methods. These methods are discussed together with…

Progression of regional grey matter atrophy in multiple sclerosis.

PubMed

Eshaghi, Arman; Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Prados, Ferran; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-06-01

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple

[Research progress on chemical constituents, pharmacological mechanism and clinical application of Guizhi decoction].

PubMed

Yuan, Hai-Jian; Li, Wei; Jin, Jian-Ming; Chen, Jing-Jing; Jiang, Jun; Wang, Hui; Jia, Xiao-Bin; Feng, Liang

2017-12-01

Guizhi Decoction was one of the most commonly used traditional Chinese Medicine which possesses the effects of "jie-ji-fa-biao, regulating Ying and Wei". It was mainly used to treat mind-cold due to exogenous evils such as fever, headache, sweating, hate the wind, et al. Modern studies indicated that the chemical constituents of Guizhi decoction mainly include phenylpropanoid, monoterpenes, organic acids, flavonoids, triterpenoid saponins and so on. Pharmacological experimental studies had shown that Guizhi decoction could play a big role in dual-directional regulation on sweat gland, body temperature, immune function, gastrointestinal peristalsis, and blood pressure, and could also play the role of anti-inflammatory, antibacterial, antiviral, anti-allergic, analgesic, hypoglycemic, and cardiovascular protection. Many diseases such as internal, external, gynecological and pediatric diseases were treated in the clinical by using Guizhi decoction and its analogous formulae involving circulatory, immune, urinary, reproductive, endocrine, digestive, nervous and other systems. This article reviews the latest research progress of Guizhi decoction from three aspects: chemical constituents, pharmacological mechanism and clinical application. It will provide reference for further research and development of Guizhi decoction. Copyright© by the Chinese Pharmaceutical Association.

The association of traumatic brain injury with rate of progression of cognitive and functional impairment in a population-based cohort of Alzheimer's disease: the Cache County Dementia Progression Study.

PubMed

Gilbert, Mac; Snyder, Christine; Corcoran, Chris; Norton, Maria C; Lyketsos, Constantine G; Tschanz, JoAnn T

2014-10-01

There is limited research on factors that influence the rate of progression in Alzheimer's disease (AD). A history of traumatic brain injury (TBI) is associated with an increased risk for AD, but its role on the rate of dementia progression after the onset of AD has not been examined. A population-based cohort of 325 persons with incident AD was followed for up to 11 years. The sample was 65% female with a mean (SD) age of dementia onset = 84.4 (6.4) years. History of TBI was categorized as number, severity (with or without loss of consciousness), and timing in relation to dementia onset (within ten years or more than ten years). Cognition was assessed by the Consortium to Establish a Registry of AD battery, and functional ability was assessed by the Clinical Dementia Rating Sum of Boxes. In linear mixed models, a history of TBI within ten years of onset showed faster progression of functional impairment (LR x2 = 10.27, p = 0.006), while those with TBI more than ten years before dementia onset had higher scores on a measure of list learning (β = 1.61, p = 0.003) and semantic memory (β = 0.75, p = 0.0035). History of TBI and its recency may be a useful factor to predict functional progression in the course of AD.

A warning to the Brazilian Speech-Language Pathology and Audiology community about the importance of scientific and clinical activities in primary progressive aphasia.

PubMed

Beber, Bárbara Costa; Brandão, Lenisa; Chaves, Márcia Lorena Fagundes

2015-01-01

This article aims to warn the Brazilian Speech-Language Pathology and Audiology scientific community about the importance and necessity of scientific and clinical activities regarding Primary Progressive Aphasia. This warning is based on a systematic literature review of the scientific production on Primary Progressive Aphasia, from which nine Brazilian articles were selected. It was observed that there is an obvious lack of studies on the subject, as all the retrieved articles were published in medical journals and much of it consisted of small samples; only two articles described the effectiveness of speech-language therapy in patients with Primary Progressive Aphasia. A perspective for the future in the area and characteristics of Speech-Language Therapy for Primary Progressive Aphasia are discussed. As a conclusion, it is evident the need for greater action by Speech-Language Pathology and Audiology on Primary Progressive Aphasia.

New clinical trial to study long-term progression of brain and spine cancers | Center for Cancer Research

Cancer.gov

Dr. Mark Gilbert, Chief, Neuro-Oncology Branch, describes an ambitious new clinical trial that, for the first time, will study the long-term progression of brain and spine cancers. The 10,000 patient trial is the largest of its kind and will follow patients throughout the course of their disease. In addition to identifying optimal treatments for common brain and spine cancers, the study focuses on treatment discovery for rare, overlooked cancers.

Practical Application of Linear Growth Measurements in Clinical Research in Low- and Middle-Income Countries

PubMed Central

Wit, Jan M.; Himes, John H.; van Buuren, Stef; Denno, Donna M.; Suchdev, Parminder S.

2017-01-01

Background/Aims Childhood stunting is a prevalent problem in low- and middle-income countries and is associated with long-term adverse neurodevelopment and health outcomes. In this review, we define indicators of growth, discuss key challenges in their analysis and application, and offer suggestions for indicator selection in clinical research contexts. Methods Critical review of the literature. Results Linear growth is commonly expressed as length-for-age or height-for-age z-score (HAZ) in comparison to normative growth standards. Conditional HAZ corrects for regression to the mean where growth changes relate to previous status. In longitudinal studies, growth can be expressed as ΔHAZ at 2 time points. Multilevel modeling is preferable when more measurements per individual child are available over time. Height velocity z-score reference standards are available for children under the age of 2 years. Adjusting for covariates or confounders (e.g., birth weight, gestational age, sex, parental height, maternal education, socioeconomic status) is recommended in growth analyses. Conclusion The most suitable indicator(s) for linear growth can be selected based on the number of available measurements per child and the child's age. By following a step-by-step algorithm, growth analyses can be precisely and accurately performed to allow for improved comparability within and between studies. PMID:28196362

Weight as predictors of clinical progression and treatment failure: results from the TREAT Asia Pediatric HIV Observational Database.

PubMed

Kariminia, Azar; Durier, Nicolas; Jourdain, Gonzague; Saghayam, Suneeta; Do, Chau V; Nguyen, Lam Van; Hansudewechakul, Rawiwan; Lumbiganon, Pagakrong; Chokephaibulkit, Kulkanya; Truong, Khanh Huu; Sirisanthana, Virat; Ung, Vibol; Vonthanak, Saphonn; Ananworanich, Jintanat; Nik Yusoff, Nik Khairulddin; Kurniati, Nia; Azahar Razali, Kamarul; Fong, Moy Siew; Nallusamy, Revathy; Wati, Dewi Kumara

2014-09-01

To evaluate the value of time-updated weight and height in predicting clinical progression, and immunological and virological failure in children receiving combination antiretroviral therapy (cART). We used Cox regression to analyze data of a cohort of Asian children. A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART. Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.

Effectiveness of concept mapping and traditional linear nursing care plans on critical thinking skills in clinical pediatric nursing course.

PubMed

Aein, Fereshteh; Aliakbari, Fatemeh

2017-01-01

Concept map is a useful cognitive tool for enhancing a student's critical thinking (CT) by encouraging students to process information deeply for understanding. However, the evidence regarding its effectiveness on nursing students' CT is contradictory. This paper compares the effectiveness of concept mapping and traditional linear nursing care planning on students' CT. An experimental design was used to examine the CT of 60 baccalaureate students who participated in pediatric clinical nursing course in the Shahrekord University of Medical Sciences, Shahrekord, Iran in 2013. Participants were randomly divided into six equal groups of each 10 student, of which three groups were the control group, and the others were the experimental group. The control group completed nine traditional linear nursing care plans, whereas experimental group completed nine concept maps during the course. Both groups showed significant improvement in overall and all subscales of the California CT skill test from pretest to posttest ( P < 0.001), but t -test demonstrated that improvement in students' CT skills in the experimental group was significantly greater than in the control group after the program ( P < 0.001). Our findings support that concept mapping can be used as a clinical teaching-learning activity to promote CT in nursing students.

Effectiveness of concept mapping and traditional linear nursing care plans on critical thinking skills in clinical pediatric nursing course

PubMed Central

Aein, Fereshteh; Aliakbari, Fatemeh

2017-01-01

Introduction: Concept map is a useful cognitive tool for enhancing a student's critical thinking (CT) by encouraging students to process information deeply for understanding. However, the evidence regarding its effectiveness on nursing students’ CT is contradictory. This paper compares the effectiveness of concept mapping and traditional linear nursing care planning on students’ CT. Methods: An experimental design was used to examine the CT of 60 baccalaureate students who participated in pediatric clinical nursing course in the Shahrekord University of Medical Sciences, Shahrekord, Iran in 2013. Results: Participants were randomly divided into six equal groups of each 10 student, of which three groups were the control group, and the others were the experimental group. The control group completed nine traditional linear nursing care plans, whereas experimental group completed nine concept maps during the course. Both groups showed significant improvement in overall and all subscales of the California CT skill test from pretest to posttest (P < 0.001), but t-test demonstrated that improvement in students’ CT skills in the experimental group was significantly greater than in the control group after the program (P < 0.001). Conclusions: Our findings support that concept mapping can be used as a clinical teaching-learning activity to promote CT in nursing students. PMID:28546978

Linear scleroderma associated with ptosis and motility disorders.

PubMed Central

Suttorp-Schulten, M S; Koornneef, L

1990-01-01

A case is reported in which an 11-year-old girl developed progressive ptosis and a subsequent motility disorder of the right eye. The diagnosis linear scleroderma en coup de sabre was established. Atrophy of the upper levator palpebral and superior rectus muscle could be shown on CT scan. Images PMID:2223709

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

PubMed

Schobel, Scott A; Palermo, Giuseppe; Auinger, Peggy; Long, Jeffrey D; Ma, Shiyang; Khwaja, Omar S; Trundell, Dylan; Cudkowicz, Merit; Hersch, Steven; Sampaio, Cristina; Dorsey, E Ray; Leavitt, Blair R; Kieburtz, Karl D; Sevigny, Jeffrey J; Langbehn, Douglas R; Tabrizi, Sarah J

2017-12-12

To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures. © 2017 American Academy of Neurology.

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

PubMed Central

Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

2016-01-01

The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.

PubMed

Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

2016-04-19

The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for transportation...

40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for transportation...

40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for transportation...

40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for transportation...

The Clinical Presentation of Mitochondrial Diseases in Children with Progressive Intellectual and Neurological Deterioration: A National, Prospective, Population-Based Study

ERIC Educational Resources Information Center

Verity, Christopher M.; Winstone, Anne Marie; Stellitano, Lesley; Krishnakumar, Deepa; Will, Robert; McFarland, Robert

2010-01-01

Aim: Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND). Method: Since April 1997, we have identified patients aged 16 years or younger with suspected PIND through the monthly notification card…

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

PubMed

Kieburtz, Karl; Tilley, Barbara C; Elm, Jordan J; Babcock, Debra; Hauser, Robert; Ross, G Webster; Augustine, Alicia H; Augustine, Erika U; Aminoff, Michael J; Bodis-Wollner, Ivan G; Boyd, James; Cambi, Franca; Chou, Kelvin; Christine, Chadwick W; Cines, Michelle; Dahodwala, Nabila; Derwent, Lorelei; Dewey, Richard B; Hawthorne, Katherine; Houghton, David J; Kamp, Cornelia; Leehey, Maureen; Lew, Mark F; Liang, Grace S Lin; Luo, Sheng T; Mari, Zoltan; Morgan, John C; Parashos, Sotirios; Pérez, Adriana; Petrovitch, Helen; Rajan, Suja; Reichwein, Sue; Roth, Jessie Tatsuno; Schneider, Jay S; Shannon, Kathleen M; Simon, David K; Simuni, Tanya; Singer, Carlos; Sudarsky, Lewis; Tanner, Caroline M; Umeh, Chizoba C; Williams, Karen; Wills, Anne-Marie

2015-02-10

There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

PubMed

Strauss, Rupert W; Muñoz, Beatriz; Ho, Alexander; Jha, Anamika; Michaelides, Michel; Cideciyan, Artur V; Audo, Isabelle; Birch, David G; Hariri, Amir H; Nittala, Muneeswar G; Sadda, SriniVas; West, Sheila; Scholl, Hendrik P N

2017-11-01

Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study. A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable. Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence. A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of

Clinical, biological, and skin histopathologic effects of ionic macrocyclic and nonionic linear gadolinium chelates in a rat model of nephrogenic systemic fibrosis.

PubMed

Fretellier, Nathalie; Idée, Jean-Marc; Guerret, Sylviane; Hollenbeck, Claire; Hartmann, Daniel; González, Walter; Robic, Caroline; Port, Marc; Corot, Claire

2011-02-01

the purpose of this study was to compare the clinical, pathologic, and biochemical effects of repeated administrations of ionic macrocyclic or nonionic linear gadolinium chelates (GC) in rats with impaired renal function. rats submitted to subtotal nephrectomy were allocated to single injections of 2.5 mmol/kg of gadodiamide (nonionic linear chelate), nonformulated gadodiamide (ie, without the free ligand caldiamide), gadoterate (ionic macrocyclic chelate), or saline for 5 consecutive days. Blinded semi-quantitative histopathologic and immunohistochemical examinations of the skin were performed, as well as clinical, hematological, and biochemical follow-up. Rats were killed at day 11. Long-term (up to day 32) follow-up of rats was also performed in an auxiliary study. epidermal lesions (ulcerations and scabs) were found in 4 of the 10 rats treated with nonformulated gadodiamide. Two rats survived the study period. Inflammatory signs were observed in this group. No clinical, hematological, or biochemical signs were observed in the saline and gadoterate- or gadodiamide-treated groups. Plasma fibroblast growth factor-23 levels were significantly higher in the gadodiamide group than in the gadoterate group (day 11). Decreased plasma transferrin-bound iron levels were measured in the nonformulated gadodiamide group. Histologic lesions were in the range: nonformulated gadodiamide (superficial epidermal lesions, inflammation, necrosis, and increased cellularity in papillary dermis) > gadodiamide (small superficial epidermal lesions and signs of degradation of collagen fibers in the dermis) > gadoterate (very few pathologic lesions, similar to control rats). repeated administration of the nonionic linear GC gadodiamide to renally impaired rats is associated with more severe histologic lesions and higher FGF-23 plasma levels than the macrocyclic GC gadoterate.

Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression.

PubMed

Puzanov, Igor; Amaravadi, Ravi K; McArthur, Grant A; Flaherty, Keith T; Chapman, Paul B; Sosman, Jeffrey A; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B; Lin, Paul S; Kim, Kevin B

2015-07-01

Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported. Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.

2009 Linear Collider Workshop of the Americas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seidel, Sally

The 2009 Linear Collider Workshop of the Americas was held on the campus of the University of New Mexico from 29 September to 3 October, 2009. This was a joint meeting of the American Linear Collider Physics Group and the ILC Global Design Effort. Two hundred fifty people attended. The number of scientific contributions was 333. The complete agenda, with links to all of the presentations, is available at physics.unm.edu/LCWA09/. The meeting brought together international experts as well as junior scientists, to discuss the physics potential of the linear collider and advances in detector technology. The validation of detector designsmore » was announced, and the detector design groups planned the next phase of the effort. Detector R&D teams reported on progress on many topics including calorimetry and tracking. Recent accelerator design considerations were discussed in a special session for experimentalists and theorists.« less

Pseudo progression identification of glioblastoma with dictionary learning.

PubMed

Zhang, Jian; Yu, Hengyong; Qian, Xiaohua; Liu, Keqin; Tan, Hua; Yang, Tielin; Wang, Maode; Li, King Chuen; Chan, Michael D; Debinski, Waldemar; Paulsson, Anna; Wang, Ge; Zhou, Xiaobo

2016-06-01

Although the use of temozolomide in chemoradiotherapy is effective, the challenging clinical problem of pseudo progression has been raised in brain tumor treatment. This study aims to distinguish pseudo progression from true progression. Between 2000 and 2012, a total of 161 patients with glioblastoma multiforme (GBM) were treated with chemoradiotherapy at our hospital. Among the patients, 79 had their diffusion tensor imaging (DTI) data acquired at the earliest diagnosed date of pseudo progression or true progression, and 23 had both DTI data and genomic data. Clinical records of all patients were kept in good condition. Volumetric fractional anisotropy (FA) images obtained from the DTI data were decomposed into a sequence of sparse representations. Then, a feature selection algorithm was applied to extract the critical features from the feature matrix to reduce the size of the feature matrix and to improve the classification accuracy. The proposed approach was validated using the 79 samples with clinical DTI data. Satisfactory results were obtained under different experimental conditions. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.87 for a given dictionary with 1024 atoms. For the subgroup of 23 samples, genomics data analysis was also performed. Results implied further perspective on pseudo progression classification. The proposed method can determine pseudo progression and true progression with improved accuracy. Laboring segmentation is no longer necessary because this skillfully designed method is not sensitive to tumor location. Copyright © 2016 Elsevier Ltd. All rights reserved.

Visual field progression in glaucoma: what is the specificity of the Guided Progression Analysis?

PubMed

Artes, Paul H; O'Leary, Neil; Nicolela, Marcelo T; Chauhan, Balwantray C; Crabb, David P

2014-10-01

To estimate the specificity of the Guided Progression Analysis (GPA) (Carl Zeiss Meditec, Dublin, CA) in individual patients with glaucoma. Observational cohort study. Thirty patients with open-angle glaucoma. In 30 patients with open-angle glaucoma, 1 eye (median mean deviation [MD], -2.5 decibels [dB]; interquartile range, -4.4 to -1.3 dB) was tested 12 times over 3 months (Humphrey Field Analyzer, Carl Zeiss Meditec; SITA Standard, 24-2). "Possible progression" and "likely progression" were determined with the GPA. These analyses were repeated after the order of the tests had been randomly rearranged (1000 unique permutations). Rate of false-positive alerts of "possible progression" and "likely progression" with the GPA. On average, the specificity of the GPA "likely progression" alert was high-for the entire sample, the mean rate of false-positive alerts after 10 follow-up tests was 2.6%. With "possible progression," the specificity was considerably lower (false-positive rate, 18.5%). Most important, the cumulative rate of false-positive alerts varied substantially among patients, from <1% to 80% with "possible progression" and from <0.1% to 20% with "likely progression." Factors associated with false-positive alerts were visual field variability (standard deviation of MD, Spearman's rho = 0.41, P<0.001) and the reliability indices (proportion of false-positive and false-negative responses, fixation losses, rho>0.31, P≤0.10). On average, progression criteria currently used in the GPA have high specificity, but some patients are more likely to show false-positive alerts than others. This is a natural consequence of population-based change criteria and may not matter in clinical trials and studies in which large groups of patients are compared. However, it must be considered when the GPA is used in clinical practice where specificity needs to be controlled for individual patients. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc

Learning oncogenetic networks by reducing to mixed integer linear programming.

PubMed

Shahrabi Farahani, Hossein; Lagergren, Jens

2013-01-01

Cancer can be a result of accumulation of different types of genetic mutations such as copy number aberrations. The data from tumors are cross-sectional and do not contain the temporal order of the genetic events. Finding the order in which the genetic events have occurred and progression pathways are of vital importance in understanding the disease. In order to model cancer progression, we propose Progression Networks, a special case of Bayesian networks, that are tailored to model disease progression. Progression networks have similarities with Conjunctive Bayesian Networks (CBNs) [1],a variation of Bayesian networks also proposed for modeling disease progression. We also describe a learning algorithm for learning Bayesian networks in general and progression networks in particular. We reduce the hard problem of learning the Bayesian and progression networks to Mixed Integer Linear Programming (MILP). MILP is a Non-deterministic Polynomial-time complete (NP-complete) problem for which very good heuristics exists. We tested our algorithm on synthetic and real cytogenetic data from renal cell carcinoma. We also compared our learned progression networks with the networks proposed in earlier publications. The software is available on the website https://bitbucket.org/farahani/diprog.

Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy.

PubMed

Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A; Blutke, Andreas; Krause, Sabine; Walter, Maggie C; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J

2016-09-16

Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials.

Effects of Instruction on Chinese College Students' Use of Thematic Progression in English Essays

ERIC Educational Resources Information Center

Wei, Jing

2017-01-01

Thematic progression (TP) patterns used in English leaner essays provide clues as to how they organize information and develop important concepts in their essays. This quasi-experimental research proved that instruction in TP produced positive effects on Chinese college students' use of linear progressions, constant progressions and new Themes.…

Clinical features, management and outcomes of progressive outer retinal necrosis (PORN) in southern Thailand.

PubMed

Sittivarakul, Wantanee; Aui-aree, Nipat

2009-03-01

To study the demographics, clinical features, treatment, and visual outcomes of progressive outer retinal necrosis (PORN) in a group of Thai patients. All cases of AIDS with a clinical diagnosis of PORN in a major tertiary referral hospital in southern Thailand between January 2003 and June 2007 were retrospectively reviewed. Demographic data, clinical features, treatment regimens, and visual outcomes were analyzed. Seven patients (11 eyes) were studied. The mean age was 44.7 years. The median CD4 count was 12 cells/mm3. A known history of cutaneous zoster was documented in 57% of cases. The median follow-up period was 17 weeks. Fifty-seven percent of the patients had bilateral disease. A majority of eyes (45.4%) had initial visual acuity of less than 20/50 to equal to or better than 20/200. About two-thirds of the eyes had anterior chamber cells. Vitritis and retinal lesions scattered throughout both posterior pole and peripheral retina were found in 72.7%. Either intravenous acyclovir in combination with intravitreal ganciclovir injections or intravenous aclyclovir alone was used for initial treatment. Retinal detachment occurred in 54.5%. Final visual acuity worsened (loss of 3 lines on the ETDRS chart or more) in 60%. Visual acuity was no light perception in 45.5% at the final recorded follow-up. Demographics, clinical features and treatment outcomes of PORN in this group of Thai patients were comparable with studies from other countries. Visual prognosis is still poor with current treatment regimens.

Investigation of Ion Beam Production and Acceleration Using Linear Electron Beams and a Pulse Powered Plasma Focus.

DTIC Science & Technology

1984-03-01

POWERED PLASMA FOCUS Contract No. AFOSR-83-0145 PROGRESS REPORT For the Period April 1, 1983 through March 31, 1984 Submitted to Air Force Office of...AND ACCELERATION USING LINEAR ELECTRON BEAMS AND A PULSE POWERED PLASMA FOCUS Contract No. AFOSR-83-0145 PROGRESS REPORT For the Period April 1, 1983...Acceleration Using Linear Electron Beams and a Pulse Powered Plasma Focus " 01 €,G APRIL 1, 1983 THROUGH MRCH 31, 1984 A. Collective Acceleration and Related

Tracking progress towards global drinking water and sanitation targets: A within and among country analysis.

PubMed

Fuller, James A; Goldstick, Jason; Bartram, Jamie; Eisenberg, Joseph N S

2016-01-15

Global access to safe drinking water and sanitation has improved dramatically during the Millennium Development Goal (MDG) period. However, there is substantial heterogeneity in progress between countries and inequality within countries. We assessed countries' temporal patterns in access to drinking water and sanitation using publicly available data. We then classified countries using non-linear modeling techniques as having one of the following trajectories: 100% coverage, linear growth, linear decline, no change, saturation, acceleration, deceleration, negative acceleration, or negative deceleration. We further assessed the degree to which temporal profiles follow a sigmoidal pattern and how these patterns might vary within a given country between rural and urban settings. Among countries with more than 10 data points, between 15% and 38% showed a non-linear trajectory, depending on the indicator. Overall, countries' progress followed a sigmoidal trend, but some countries are making better progress and some worse progress than would be expected. We highlight several countries that are not on track to meet the MDG for water or sanitation, but whose access is accelerating, suggesting better performance during the coming years. Conversely, we also highlight several countries that have made sufficient progress to meet the MDG target, but in which access is decelerating. Patterns were heterogeneous and non-linearity was common. Characterization of these heterogeneous patterns will help policy makers allocate resources more effectively. For example, policy makers can identify countries that could make use of additional resources or might be in need of additional institutional capacity development to properly manage resources; this will be essential to meet the forthcoming Sustainable Development Goals. Copyright © 2015 Elsevier B.V. All rights reserved.

Progression of Patterns (POP): A Machine Classifier Algorithm to Identify Glaucoma Progression in Visual Fields

PubMed Central

Goldbaum, Michael H.; Lee, Intae; Jang, Giljin; Balasubramanian, Madhusudhanan; Sample, Pamela A.; Weinreb, Robert N.; Liebmann, Jeffrey M.; Girkin, Christopher A.; Anderson, Douglas R.; Zangwill, Linda M.; Fredette, Marie-Josee; Jung, Tzyy-Ping; Medeiros, Felipe A.; Bowd, Christopher

2012-01-01

Purpose. We evaluated Progression of Patterns (POP) for its ability to identify progression of glaucomatous visual field (VF) defects. Methods. POP uses variational Bayesian independent component mixture model (VIM), a machine learning classifier (MLC) developed previously. VIM separated Swedish Interactive Thresholding Algorithm (SITA) VFs from a set of 2,085 normal and glaucomatous eyes into nine axes (VF patterns): seven glaucomatous. Stable glaucoma was simulated in a second set of 55 patient eyes with five VFs each, collected within four weeks. A third set of 628 eyes with 4,186 VFs (mean ± SD of 6.7 ± 1.7 VFs over 4.0 ± 1.4 years) was tested for progression. Tested eyes were placed into suspect and glaucoma categories at baseline, based on VFs and disk stereoscopic photographs; a subset of eyes had stereophotographic evidence of progressive glaucomatous optic neuropathy (PGON). Each sequence of fields was projected along seven VIM glaucoma axes. Linear regression (LR) slopes generated from projections onto each axis yielded a degree of confidence (DOC) that there was progression. At 95% specificity, progression cutoffs were established for POP, visual field index (VFI), and mean deviation (MD). Guided progression analysis (GPA) was also compared. Results. POP identified a statistically similar number of eyes (P > 0.05) as progressing compared with VFI, MD, and GPA in suspects (3.8%, 2.7%, 5.6%, and 2.9%, respectively), and more eyes than GPA (P = 0.01) in glaucoma (16.0%, 15.3%, 12.0%, and 7.3%, respectively), and more eyes than GPA (P = 0.05) in PGON eyes (26.3%, 23.7%, 27.6%, and 14.5%, respectively). Conclusions. POP, with its display of DOC of progression and its identification of progressing VF defect pattern, adds to the information available to the clinician for detecting VF progression. PMID:22786913

Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schüler, Emil; Trovati, Stefania; King, Gregory

Purpose: A key factor limiting the effectiveness of radiation therapy is normal tissue toxicity, and recent preclinical data have shown that ultra-high dose rate irradiation (>50 Gy/s, “FLASH”) potentially mitigates this effect. However, research in this field has been strongly limited by the availability of FLASH irradiators suitable for small animal experiments. We present a simple methodologic approach for FLASH electron small animal irradiation with a clinically available linear accelerator (LINAC). Methods and Materials: We investigated the FLASH irradiation potential of a Varian Clinac 21EX in both clinical mode and after tuning of the LINAC. We performed detailed FLUKA Monte Carlomore » and experimental dosimetric characterization at multiple experimental locations within the LINAC head. Results: Average dose rates of ≤74 Gy/s were achieved in clinical mode, and the dose rate after tuning exceeded 900 Gy/s. We obtained 220 Gy/s at 1-cm depth for a >4-cm field size with 90% homogeneity throughout a 2-cm-thick volume. Conclusions: We present an approach for using a clinical LINAC for FLASH irradiation. We obtained dose rates exceeding 200 Gy/s after simple tuning of the LINAC, with excellent dosimetric properties for small animal experiments. This will allow for increased availability of FLASH irradiation to the general research community.« less

Post Kalman progress

NASA Technical Reports Server (NTRS)

Sonnabend, David

1995-01-01

In a paper here last year, an idea was put forward that much greater performance could be obtained from an observer, relative to a Kalman filter if more general performance indices were adopted, and the full power spectra of all the noises were employed. The considerable progress since then is reported here. Included are an extension of the theory to regulators, direct calculation of the theory's fundamental quantities - the noise effect integrals - for several theoretical spectra, and direct derivations of the Riccati equations of LQG (Linear-Quadratic-Gaussian) and Kalman theory yielding new insights.

Socio-demographic and academic correlates of clinical reasoning in a dental school in South Africa.

PubMed

Postma, T C; White, J G

2017-02-01

There are no empirical studies that describe factors that may influence the development of integrated clinical reasoning skills in dental education. Hence, this study examines the association between outcomes of clinical reasoning in relation with differences in instructional design and student factors. Progress test scores, including diagnostic and treatment planning scores, of fourth and fifth year dental students (2009-2011) at the University of Pretoria, South Africa served as the outcome measures in stepwise linear regression analyses. These scores were correlated with the instructional design (lecture-based teaching and learning (LBTL = 0) or case-based teaching and learning (CBTL = 1), students' grades in Oral Biology, indicators of socio-economic status (SES) and gender. CBTL showed an independent association with progress test scores. Oral Biology scores correlated with diagnostic component scores. Diagnostic component scores correlated with treatment planning scores in the fourth year of study but not in the fifth year of study. 'SES' correlated with progress test scores in year five only, while gender showed no correlation. The empirical evidence gathered in this study provides support for scaffolded inductive teaching and learning methods to develop clinical reasoning skills. Knowledge in Oral Biology and reading skills may be important attributes to develop to ensure that students are able to reason accurately in a clinical setting. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Thematic Progression Analysis in Teaching Explanation Writing

ERIC Educational Resources Information Center

Yang, Xueqian

2008-01-01

Thematic Progression theory explains textual meanings of how experiential and interpersonal meanings are organized in a linear and coherent way. Employing the rationale of T-P theory, this article analyses a lesson plan of teaching Explanation, and shows that T-P analysis can be employed in teaching writing.

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.

PubMed

Takei, Koji; Tsuda, Kikumi; Takahashi, Fumihiro; Hirai, Manabu; Palumbo, Joseph

2017-10-01

There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.

Disease progression and neuroscience.

PubMed

Holford, Nick

2013-06-01

The concepts of disease progression are discussed in the context of neurological disorders. The importance of understanding the time course of the response to inactive (placebo) treatment is discussed. Disease progression and response to placebo treatment both need to be considered before drug effects can be reliably identified. Criteria for distinguishing between symptomatic and disease modifying drug effects are proposed and used to interpret the results of clinical trials in pain, depression, schizophrenia, stroke, Alzheimer's disease and Parkinson's disease.

DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease.

PubMed

Pernat Drobež, Cvetka; Repnik, Katja; Gorenjak, Mario; Ferkolj, Ivan; Weersma, Rinse K; Potočnik, Uroš

2018-04-01

Most patients with Crohn's disease (CD) are diagnosed with the uncomplicated inflammatory form of the disease (Montreal stage B1). However, the majority of them will progress to complicated stricturing (B2) and penetrating (B3) CD during their lifetimes. The aim of our study was to identify the genetic factors associated with time to progression from uncomplicated to complicated CD. Patients with an inflammatory phenotype at diagnosis were followed up for 10 years. Genotyping was carried out using Illumina ImmunoChip. After quality control, association analyses, Bonferroni's adjustments, linear and Cox's regression, and Kaplan-Meier analysis were carried out for 111 patients and Manhattan plots were constructed. Ten years after diagnosis, 39.1% of the patients still had the inflammatory form and 60.9% progressed to complicated disease, with an average time to progression of 5.91 years. Ileal and ileocolonic locations were associated with the complicated CD (P=1.08E-03). We found that patients with the AA genotype at single-nucleotide polymorphism rs16857259 near the gene CACNA1E progressed to the complicated form later (8.80 years) compared with patients with the AC (5.11 years) or CC (2.00 years) genotypes (P=3.82E-07). In addition, nine single-nucleotide polymorphisms (near the genes RASGRP1, SULF2, XPO1, ZBTB44, HLA DOA/BRD2, HLA DRB1/HLA DQA1, PPARA, PUDP, and KIAA1614) showed a suggestive association with disease progression (P<10). Multivariate Cox's regression analysis on the basis of clinical and genetic data confirmed the association of the selected model with disease progression (P=5.73E-16). Our study confirmed the association between the locus on chromosome 1 near the gene CACNA1E with time to progression from inflammatory to stricturing or penetrating CD. Predicting the time to progression is useful to the clinician in terms of individualizing patients' management.

Discordance between 'actual' and 'scheduled' check-in times at a heart failure clinic

PubMed Central

Joyce, Emer; Gandesbery, Benjamin T.; Blackstone, Eugene H.; Taylor, David O.; Tang, W. H. Wilson; Starling, Randall C.; Hachamovitch, Rory

2017-01-01

Introduction A 2015 Institute Of Medicine statement “Transforming Health Care Scheduling and Access: Getting to Now”, has increased concerns regarding patient wait times. Although waiting times have been widely studied, little attention has been paid to the role of patient arrival times as a component of this phenomenon. To this end, we investigated patterns of patient arrival at scheduled ambulatory heart failure (HF) clinic appointments and studied its predictors. We hypothesized that patients are more likely to arrive later than scheduled, with progressively later arrivals later in the day. Methods and results Using a business intelligence database we identified 6,194 unique patients that visited the Cleveland Clinic Main Campus HF clinic between January, 2015 and January, 2017. This clinic served both as a tertiary referral center and a community HF clinic. Transplant and left ventricular assist device (LVAD) visits were excluded. Punctuality was defined as the difference between ‘actual’ and ‘scheduled’ check-in times, whereby negative values (i.e., early punctuality) were patients who checked-in early. Contrary to our hypothesis, we found that patients checked-in late only a minority of the time (38% of visits). Additionally, examining punctuality by appointment hour slot we found that patients scheduled after 8AM had progressively earlier check-in times as the day progressed (P < .001 for trend). In both a Random Forest-Regression framework and linear regression models the most important risk-adjusted predictors of early punctuality were: later in the day appointment hour slot, patient having previously been to the hospital, age in the early 70s, and white race. Conclusions Patients attending a mixed population ambulatory HF clinic check-in earlier than scheduled times, with progressive discrepant intervals throughout the day. This finding may have significant implications for provider utilization and resource planning in order to maximize clinic

Towards local progression estimation of pulmonary emphysema using CT.

PubMed

Staring, M; Bakker, M E; Stolk, J; Shamonin, D P; Reiber, J H C; Stoel, B C

2014-02-01

Whole lung densitometry on chest CT images is an accepted method for measuring tissue destruction in patients with pulmonary emphysema in clinical trials. Progression measurement is required for evaluation of change in health condition and the effect of drug treatment. Information about the location of emphysema progression within the lung may be important for the correct interpretation of drug efficacy, or for determining a treatment plan. The purpose of this study is therefore to develop and validate methods that enable the local measurement of lung density changes, which requires proper modeling of the effect of respiration on density. Four methods, all based on registration of baseline and follow-up chest CT scans, are compared. The first naïve method subtracts registered images. The second employs the so-called dry sponge model, where volume correction is performed using the determinant of the Jacobian of the transformation. The third and the fourth introduce a novel adaptation of the dry sponge model that circumvents its constant-mass assumption, which is shown to be invalid. The latter two methods require a third CT scan at a different inspiration level to estimate the patient-specific density-volume slope, where one method employs a global and the other a local slope. The methods were validated on CT scans of a phantom mimicking the lung, where mass and volume could be controlled. In addition, validation was performed on data of 21 patients with pulmonary emphysema. The image registration method was optimized leaving a registration error below half the slice increment (median 1.0 mm). The phantom study showed that the locally adapted slope model most accurately measured local progression. The systematic error in estimating progression, as measured on the phantom data, was below 2 gr/l for a 70 ml (6%) volume difference, and 5 gr/l for a 210 ml (19%) difference, if volume correction was applied. On the patient data an underlying linearity assumption

Progression of regional grey matter atrophy in multiple sclerosis

PubMed Central

Marinescu, Razvan V; Young, Alexandra L; Firth, Nicholas C; Jorge Cardoso, M; Tur, Carmen; De Angelis, Floriana; Cawley, Niamh; Brownlee, Wallace J; De Stefano, Nicola; Laura Stromillo, M; Battaglini, Marco; Ruggieri, Serena; Gasperini, Claudio; Filippi, Massimo; Rocca, Maria A; Rovira, Alex; Sastre-Garriga, Jaume; Geurts, Jeroen J G; Vrenken, Hugo; Wottschel, Viktor; Leurs, Cyra E; Uitdehaag, Bernard; Pirpamer, Lukas; Enzinger, Christian; Ourselin, Sebastien; Gandini Wheeler-Kingshott, Claudia A; Chard, Declan; Thompson, Alan J; Barkhof, Frederik; Alexander, Daniel C; Ciccarelli, Olga

2018-01-01

Abstract See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article. Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse

Progression of Liver Disease

MedlinePlus

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A pharmaco-metabolomics approach in a clinical trial of ALS: Identification of predictive markers of progression.

PubMed

Blasco, Hélène; Patin, Franck; Descat, Amandine; Garçon, Guillaume; Corcia, Philippe; Gelé, Patrick; Lenglet, Timothée; Bede, Peter; Meininger, Vincent; Devos, David; Gossens, Jean François; Pradat, Pierre-François

2018-01-01

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

PubMed

Parikh, Asit; Stephens, Kristin; Major, Eugene; Fox, Irving; Milch, Catherine; Sankoh, Serap; Lev, Michael H; Provenzale, James M; Shick, Jesse; Patti, Mark; McAuliffe, Megan; Berger, Joseph R; Clifford, David B

2018-05-08

Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes

PubMed Central

2012-01-01

Introduction Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome. Methods Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models. Results Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome. Conclusions Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials. PMID:23036105

Linear and non-linear interdependence of EEG and HRV frequency bands in human sleep.

PubMed

Chaparro-Vargas, Ramiro; Dissanayaka, P Chamila; Patti, Chanakya Reddy; Schilling, Claudia; Schredl, Michael; Cvetkovic, Dean

2014-01-01

The characterisation of functional interdependencies of the autonomic nervous system (ANS) stands an evergrowing interest to unveil electroencephalographic (EEG) and Heart Rate Variability (HRV) interactions. This paper presents a biosignal processing approach as a supportive computational resource in the estimation of sleep dynamics. The application of linear, non-linear methods and statistical tests upon 10 overnight polysomnographic (PSG) recordings, allowed the computation of wavelet coherence and phase locking values, in order to identify discerning features amongst the clinical healthy subjects. Our findings showed that neuronal oscillations θ, α and σ interact with cardiac power bands at mid-to-high rank of coherence and phase locking, particularly during NREM sleep stages.

Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative

PubMed Central

Samtani, Mahesh N; Raghavan, Nandini; Novak, Gerald; Nandy, Partha; Narayan, Vaibhav A

2014-01-01

Background The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) scores. These were derived from the Alzheimer’s Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications. Results Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations. PMID:24926196

Does erosion progress differently on teeth already presenting clinical signs of erosive tooth wear than on sound teeth? An in vitro pilot trial.

PubMed

Carvalho, Thiago Saads; Baumann, Tommy; Lussi, Adrian

2016-07-07

Erosive tooth wear (ETW) is clinically characterized by a loss of tooth surface, and different enamel depths may have different susceptibility to demineralization. Therefore, the aim of this in vitro pilot study was to assess if the progression of erosive demineralization is faster on teeth already presenting signs of ETW when compared to originally sound teeth. We selected 23 central incisors: 14 were clinically sound (Sound) and 9 presented clinical signs of early erosive tooth wear (ETW-teeth). The teeth were embedded in resin, leaving an uncovered window of native enamel (6.69 ± 2.30 mm(2)) on the incisal half of the labial surface. We measured enamel surface reflection intensity (SRI) initially and after each consecutive erosive challenge (1 % citric acid, total of 4, 8, 12, 16, 20 and 24 min). Calcium released to the citric acid was measured with an atomic absorption spectrometer. We observed higher initial SRI values in ETW-teeth than in Sound teeth (p = 0.007). During in vitro erosive demineralization, we observed that erosion on originally Sound teeth progressed significantly slower (p = 0.033) than on ETW-teeth: SRI decreased by 75 % (from 100 to 25 %) on Sound teeth, and by 89 % (from 100 to 11 %) on ETW-teeth. Calcium release increased during erosion, but presented no significant differences (p = 0.643) between originally Sound (0.031 μmol/mm(2)) and ETW-teeth (0.032 μmol/mm(2)). There was satisfactory correlation between calcium release and rSRI values (r s  = -0.66). The optical reflectometer distinguished originally sound teeth from those with signs of ETW, and the results suggest that acid demineralization progresses differently on teeth already presenting clinical signs of ETW than on sound teeth.

Factors that influence career progression among postdoctoral clinical academics: a scoping review of the literature

PubMed Central

Ranieri, Veronica; Barratt, Helen; Fulop, Naomi; Rees, Geraint

2016-01-01

Background The future of academic medicine is uncertain. Concerns regarding the future availability of qualified and willing trainee clinical academics have been raised worldwide. Of significant concern is our failure to retain postdoctoral trainee clinical academics, who are likely to be our next generation of leaders in scientific discovery. Objectives To review the literature about factors that may influence postdoctoral career progression in early career clinical academics. Design This study employed a scoping review method. Three reviewers separately assessed whether the articles found fit the inclusion criteria. Data sources PubMed, Scopus, Web of Science and Google Scholar (1991–2015). Article selection The review encompassed a broad search of English language studies published anytime up to November 2015. All articles were eligible for inclusion, including research papers employing either quantitative or qualitative methods, as well as editorials and other summary articles. Data extraction Data extracted from included publications were charted according to author(s), sample population, study design, key findings, country of origin and year of publication. Results Our review identified 6 key influences: intrinsic motivation, work–life balance, inclusiveness, work environment, mentorship and availability of funding. It also detected significant gaps within the literature about these influences. Conclusions Three key steps are proposed to help support postdoctoral trainee clinical academics. These focus on ensuring that researchers feel encouraged in their workplace, involved in collaborative dialogue with key stakeholders and able to access reliable information regarding their chosen career pathway. Finally, we highlight recommendations for future research. PMID:27798036

Thematic Progression in a Cardiologist's Text: Context, Frames and Progression.

ERIC Educational Resources Information Center

Salter, Robert T.

Thematic progression (TP) is examined in the text of a communication between a cardiologist and a general practitioner concerning a patient, offering a clinical diagnosis of the patient's condition. Analysis of the discourse looks at the field, tenor, and mode of the communication as a context for TP. The methods of analysis are first described,…

Estrogens and progression of diabetic kidney damage.

PubMed

Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Elliot, Sharon J

2011-01-01

It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

PubMed

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Cortical neuroanatomic correlates of symptom severity in primary progressive aphasia

PubMed Central

Sapolsky, D.; Bakkour, A.; Negreira, A.; Nalipinski, P.; Weintraub, S.; Mesulam, M.-M.; Caplan, D.; Dickerson, B.C.

2010-01-01

Objective: To test the validity and reliability of a new measure of clinical impairment in primary progressive aphasia (PPA), the Progressive Aphasia Severity Scale (PASS), and to investigate relationships with MRI-based cortical thickness biomarkers for localizing and quantifying the severity of anatomic abnormalities. Methods: Patients with PPA were rated using the PASS and underwent performance-based language testing and MRI scans that were processed for cortical thickness measures. Results: The level of impairment in PASS fluency, syntax/grammar, and word comprehension showed strong specific correlations with performance-based measures of these domains of language, and demonstrated high interrater reliability. Left inferior frontal thinning correlated with impairment in fluency and grammar/syntax, while left temporopolar thinning correlated with impairment in word comprehension. Discriminant function analysis demonstrated that a combination of left inferior frontal, left temporopolar, and left superior temporal sulcal thickness separated the 3 PPA subtypes from each other with 100% accuracy (87% accuracy in a leave-one-out analysis). Conclusions: The PASS, a novel measure of the severity of clinical impairment within domains of language typically affected in PPA, demonstrates reliable and valid clinical-behavioral properties. Furthermore, the presence of impairment in individual PASS domains demonstrates specific relationships with focal abnormalities in particular brain regions and the severity of impairment is strongly related to the severity of anatomic abnormality within the relevant brain region. These anatomic imaging biomarkers perform well in classifying PPA subtypes. These data provide robust support for the value of this novel clinical measure and the new imaging measure as markers for potential use in clinical research and trials in PPA. GLOSSARY AD = Alzheimer disease; BDAE = Boston Diagnostic Aphasia Examination; CDR = Clinical Dementia Rating; CSB

Rosuvastatin Slows Progression of Subclinical Atherosclerosis in Patients with Treated HIV Infection

PubMed Central

Longenecker, Chris T.; Sattar, Abdus; Gilkeson, Robert; Mccomsey, Grace A.

2016-01-01

Objective To determine the effect of statins on the progression of subclinical atherosclerosis in a population of HIV-infected adults on antiretroviral therapy. Design Double-blind, randomized clinical trial Methods SATURN-HIV was a 96-week double-blind, randomized clinical trial of 10 mg daily rosuvastatin (n=72) versus placebo (n=75) in a population of HIV-infected subjects on stable antiretroviral therapy with LDL-cholesterol ≤130mg/dL (≤3.36mmol/L) and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2mg/L (≥19mmol/L)). Change in common carotid artery IMT (CCA-IMT) was the primary outcome. Secondary outcomes were changes in LDL and coronary artery calcium (CAC). Results Median (Q1, Q3) age was 46 (40, 53) years; 78% were male and 68% African American; 49% were on a protease inhibitor. Mean (95% CI) change in LDL was −21 (−27 to −15) mg/dL [−0.54 (−0.70 to −0.39) mmol/L] in the rosuvastatin arm. In a multivariable linear mixed-effects model, assignment to statin was associated with 0.019mm (95% CI: 0.002–0.037mm) less progression of CCA-IMT over 96 weeks. We did not find substantial effect modification by level of inflammation or immune activation biomarkers, except for a borderline statistically significant interaction for soluble vascular cell adhesion molecule (p=0.065). There was no difference in CAC change (p=0.61). Conclusions Rosuvastatin effectively lowers LDL and appears to substantially slow progression of CCA-IMT in patients with treated HIV infection. Future study is needed to determine whether subjects with higher levels of inflammation or immune activation derive greater cardiovascular benefit from statin therapy. PMID:27203715

Linear Cowden nevus: a new distinct epidermal nevus.

PubMed

Happle, Rudolf

2007-01-01

Within the group of epidermal nevi, a so far nameless disorder is described under the term "linear Cowden nevus". This non-organoid epidermal nevus is caused by loss of heterozygosity, occurring at an early developmental stage in an embryo with a germline PTEN mutation, giving rise to Cowden disease. Hence, linear Cowden nevus can be categorized as a characteristic feature of type 2 segmental Cowden disease. Until now, several authors had mistaken this epidermal nevus as a manifestation of Proteus syndrome. The concept of linear Cowden nevus implies that Proteus syndrome is by no means caused by PTEN mutations. As a clinical difference, linear Cowden nevus is markedly papillomatous and thick, whereas linear Proteus nevus tends to be rather flat. Moreover, the spectrum of possibly associated cutaneous or extracutaneous anomalies differs in the two types of nevi. In conclusion, linear Cowden nevus, that may also be called "linear PTEN nevus", represents a distinct clinicogenetic entity.

Progression of white matter damage in progressive supranuclear palsy with predominant parkinsonism.

PubMed

Caso, Francesca; Agosta, Federica; Ječmenica-Lukić, Milica; Petrović, Igor; Meani, Alessandro; Kostic, Vladimir S; Filippi, Massimo

2018-04-01

Progressive supranuclear palsy with predominant parkinsonism (PSP-P) accounts for 14-35% of all PSP cases. A few cross-sectional MRI studies in PSP-P showed a remarkable white matter (WM) damage. Progression of brain structural damage in these patients remains unknown. Longitudinal clinical, cognitive and diffusion tensor (DT) MRI data were obtained over a mean 1.6 year follow up in 10 PSP-P patients. At study entry, patients were compared with 36 healthy controls. Voxelwise statistical analysis of white matter DT MRI data (mean, axial and radial diffusivity, and fractional anisotropy) was carried out using tract-based spatial statistics. During the 1.6 year follow up, PSP-P patients showed significant decline of motor, cognitive and mood disturbances. DT MRI analysis revealed at baseline a widespread pattern of WM alterations. Over time, PSP-P patients exhibited progression of WM damage in supratentorial tracts compared to baseline. No WM changes were detected in cerebellar WM. In PSP-P patients, WM damage significantly progressed over time. Longitudinal DT MRI measures are a potential in vivo marker of disease progression in PSP-P. Copyright © 2018 Elsevier Ltd. All rights reserved.

TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort

PubMed Central

Molnar, Christoph; Scherer, Almut; de Hooge, Manouk; Micheroli, Raphael; Exer, Pascale; Kissling, Rudolf O; Tamborrini, Giorgio; Wildi, Lukas M; Nissen, Michael J; Zufferey, Pascal; Bernhard, Jürg; Weber, Ulrich; Landewé, Robert B M; Ciurea, Adrian

2018-01-01

Objectives To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS). Methods Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis. Results A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97). Conclusion TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity. PMID:28939631

Detection of clinically relevant copy number alterations in oral cancer progression using multiplexed droplet digital PCR.

PubMed

Hughesman, Curtis B; Lu, X J David; Liu, Kelly Y P; Zhu, Yuqi; Towle, Rebecca M; Haynes, Charles; Poh, Catherine F

2017-09-19

Copy number alterations (CNAs), a common genomic event during carcinogenesis, are known to affect a large fraction of the genome. Common recurrent gains or losses of specific chromosomal regions occur at frequencies that they may be considered distinctive features of tumoral cells. Here we introduce a novel multiplexed droplet digital PCR (ddPCR) assay capable of detecting recurrent CNAs that drive tumorigenesis of oral squamous cell carcinoma. Applied to DNA extracted from oral cell lines and clinical samples of various disease stages, we found good agreement between CNAs detected by our ddPCR assay with those previously reported using comparative genomic hybridization or single nucleotide polymorphism arrays. Furthermore, we demonstrate that the ability to target specific locations of the genome permits detection of clinically relevant oncogenic events such as small, submicroscopic homozygous deletions. Additional capabilities of the multiplexed ddPCR assay include the ability to infer ploidy level, quantify the change in copy number of target loci with high-level gains, and simultaneously assess the status and viral load for high-risk human papillomavirus types 16 and 18. This novel multiplexed ddPCR assay therefore may have clinical value in differentiating between benign oral lesions from those that are at risk of progressing to oral cancer.

Does psychological stress in patients with clinically suspect arthralgia associate with subclinical inflammation and progression to inflammatory arthritis?

PubMed

Boer, Aleid C; Ten Brinck, Robin M; Evers, Andrea W M; van der Helm-van Mil, Annette H M

2018-05-03

Within established rheumatoid arthritis (RA), stress can have pro-inflammatory effects by activating the immune system via the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. It is unknown if stress levels also promote inflammation during RA development. We studied whether the psychological stress response was increased in clinically suspect arthralgia (CSA) and if this associated with inflammation at presentation with arthralgia and with progression to clinical arthritis. In 241 CSA patients, psychological stress was measured by the Mental Health Inventory (MHI-5) and the Perceived Stress Scale (PSS-10) at first presentation and during follow-up. Systemic inflammation was measured by C-reactive protein (CRP) and joint inflammation by 1.5 T-MRI of wrist, MCP, and MTP joints. At baseline, 12% (24/197) of CSA patients had a high psychological stress response according to the MHI-5. This was not different for patients presenting with or without an elevated CRP, with or without subclinical MRI-detected inflammation and for patients who did or did not develop arthritis. Similar findings were obtained with the PSS-10. When developing clinical arthritis, the percentage of patients with 'high psychological stress' increased to 31% (p = 0.025); during the first year of treatment this decreased to 8% (p = 0.020). 'High psychological stress' in non-progressors remained infrequent over time (range 7-13%). Stress was associated with fatigue (p = 0.003) and wellbeing (p < 0.001). Psychological stress was not increased in the phase of arthralgia, raised at the time of diagnoses and decreased thereafter. The lack of an association with inflammation in arthralgia and this temporal relationship, argue against psychological stress having a significant contribution to progression from CSA to inflammatory arthritis.

The progress test as a diagnostic tool for a new PBL curriculum.

PubMed

Al Alwan, I; Al-Moamary, M; Al-Attas, N; Al Kushi, A; AlBanyan, E; Zamakhshary, M; Al Kadri, H M F; Tamim, H; Magzoub, M; Hajeer, A; Schmidt, H

2011-12-01

The College of Medicine at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) is running a PBL-based curriculum. A progress test was used to evaluate components of the basic medical and clinical sciences curriculum. To evaluate the performance of students at different levels of the college of medicine curriculum through USMLE-based test that focused on basic medical and clinical sciences topics. The USMLE-based basic medical and clinical sciences progress test has been conducted since 2007. It covers nine topics, including: anatomy; physiology; histology; epidemiology; biochemistry; behavioral sciences, pathology, pharmacology and immunology/microbiology. Here we analyzed results of three consecutive years of all students in years 1-4. There was a good correlation between progress test results and students' GPA. Progress test results in the clinical topics were better than basic medical sciences. In basic medical sciences, results of pharmacology, biochemistry, behavioral sciences and histology gave lower results than the other disciplines. Results of our progress test proved to be a useful indicator for both basic medical sciences and clinical sciences curriculum. Results are being utilized to help in modifying our curriculum.

Imaging outcome measures for progressive multiple sclerosis trials

PubMed Central

Moccia, Marcello; de Stefano, Nicola; Barkhof, Frederik

2017-01-01

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation. PMID:29041865

Unsupervised Gaussian Mixture-Model With Expectation Maximization for Detecting Glaucomatous Progression in Standard Automated Perimetry Visual Fields.

PubMed

Yousefi, Siamak; Balasubramanian, Madhusudhanan; Goldbaum, Michael H; Medeiros, Felipe A; Zangwill, Linda M; Weinreb, Robert N; Liebmann, Jeffrey M; Girkin, Christopher A; Bowd, Christopher

2016-05-01

To validate Gaussian mixture-model with expectation maximization (GEM) and variational Bayesian independent component analysis mixture-models (VIM) for detecting glaucomatous progression along visual field (VF) defect patterns (GEM-progression of patterns (POP) and VIM-POP). To compare GEM-POP and VIM-POP with other methods. GEM and VIM models separated cross-sectional abnormal VFs from 859 eyes and normal VFs from 1117 eyes into abnormal and normal clusters. Clusters were decomposed into independent axes. The confidence limit (CL) of stability was established for each axis with a set of 84 stable eyes. Sensitivity for detecting progression was assessed in a sample of 83 eyes with known progressive glaucomatous optic neuropathy (PGON). Eyes were classified as progressed if any defect pattern progressed beyond the CL of stability. Performance of GEM-POP and VIM-POP was compared to point-wise linear regression (PLR), permutation analysis of PLR (PoPLR), and linear regression (LR) of mean deviation (MD), and visual field index (VFI). Sensitivity and specificity for detecting glaucomatous VFs were 89.9% and 93.8%, respectively, for GEM and 93.0% and 97.0%, respectively, for VIM. Receiver operating characteristic (ROC) curve areas for classifying progressed eyes were 0.82 for VIM-POP, 0.86 for GEM-POP, 0.81 for PoPLR, 0.69 for LR of MD, and 0.76 for LR of VFI. GEM-POP was significantly more sensitive to PGON than PoPLR and linear regression of MD and VFI in our sample, while providing localized progression information. Detection of glaucomatous progression can be improved by assessing longitudinal changes in localized patterns of glaucomatous defect identified by unsupervised machine learning.

Infectious Adverse Events Following Acupuncture: Clinical Progress and Microbiological Etiology.

PubMed

Kim, Youn-Jung; Kim, Sung-Han; Lee, Hak Jin; Kim, Won Young

2018-06-11

We investigated the clinical progress and bacteriological characteristics of infectious adverse events (AEs) following acupuncture and compared patient characteristics between serious and non-serious outcome groups. A retrospective observational study was conducted in 1,174 patients with infectious complications associated with acupuncture at the emergency department (ED) in a tertiary hospital in Korea between 2010 and 2014. Serious outcome was defined as development of septic shock, admission to intensive care unit (ICU) or attaining permanent morbidity. Forty-eight patients had certain causality and cellulitis, necrotizing fasciitis and osteomyelitis were common in order. Among them, 9 patients (18.8%) were categorized into serious outcome group, and they showed devastating outcomes such as septic shock (n = 2), ICU admission (n = 4), and permanent sequelae (n = 5). The serious group had delayed admission to the ED after acupuncture (30.0 [4.0-55.0] vs. 3.0 [1.0-10.0] days, P = 0.023). Methicillin-sensitive Staphylococcus aureus was the most frequently identified microorganism. The patients in the serious group required longer treatment duration (139.0 [49.0-183.5] vs. 14.0 [7.0-34.0] days, P < 0.001) as well as more operation with local (44.4% vs. 10.3%, P = 0.031) or general anaesthesia (33.3% vs. 2.6%, P = 0.017). The infectious AEs after acupuncture may cause serious outcomes. Patients and primary physicians should be aware of the risk of infectious complications and make efforts to prevent them.

Progressive ataxia in a Charolais bull.

PubMed

Zicker, S C; Kasari, T R; Scruggs, D W; Read, W K; Edwards, J F

1988-06-01

A 20-month-old Charolais bull was referred for evaluation of progressive hind limb ataxia. Clinical findings suggested a neuroanatomic lesion caudal to T2. Postmortem histologic examination revealed multifocal, acellular, pale, eosinophilic plaques throughout the cerebellum, which were diagnostic for the disease progressive ataxia of Charolais cattle. This disease is presumed to have a hereditary transmission and is not commonly recognized in the United States.

Gerstmann-Straeussler-Scheinker disease with P102L prion protein gene mutation presenting with rapidly progressive clinical course.

PubMed

Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Nokura, Kazuya; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

2014-01-01

We describe an autopsied case of a Japanese woman with Gerstmann-Straeussler-Scheinker disease (GSS) presenting with a rapidly progressive clinical course. Disease onset occurred at the age of 54 with dementia and gait disturbance. Her clinical course progressively deteriorated until she reached a bedridden state with myoclonus 9 months after onset. Two months later, she reached the akinetic mutism state. Nasal tube feeding was introduced at this point and continued for several years. Electroencephalograms showed diffuse slowing without periodic sharp-wave complexes. Diffusion-weighted magnetic resonance imaging (MRI) showed widespread cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed a Pro to Leu point mutation at codon 102 with methionine homozygosity at codon 129. The patient died of respiratory failure after a total disease duration of 62 months. Neuropathologic examination revealed widespread spongiform change with numerous eosinophilic amyloid plaques (Kuru plaques) in the cerebral and cerebellar cortices by H & E staining. Diffuse myelin pallor with axon loss of the cerebral white matter, suggestive of panencephalopathic-type pathology was observed. Numerous PrP immunopositive plaques and diffuse synaptic-type PrP deposition were extensively observed, particularly in the cerebral and cerebellar cortices. Western blot analysis of proteinase Kresistant PrP showed a characteristic band pattern with a small molecular band of 6 kDa. The reason for the similarity in clinicopathologic findings between the present case and Creutzfeldt-Jakob disease is uncertain; however, the existence of an unknown disease-modifying factor is suspected.

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models.

PubMed

Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-09-01

To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87-97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4-5 months and sites recovered with a high probability (96-98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. © 2014 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

Clinical, cognitive, and behavioural correlates of white matter damage in progressive supranuclear palsy.

PubMed

Agosta, Federica; Galantucci, Sebastiano; Svetel, Marina; Lukić, Milica Ječmenica; Copetti, Massimiliano; Davidovic, Kristina; Tomić, Aleksandra; Spinelli, Edoardo G; Kostić, Vladimir S; Filippi, Massimo

2014-05-01

White matter (WM) tract alterations were assessed in patients with progressive supranuclear palsy (PSP) relative to healthy controls and patients with idiopathic Parkinson's disease (PD) to explore the relationship of WM tract damage with clinical disease severity, performance on cognitive tests, and apathy. 37 PSP patients, 41 PD patients, and 34 healthy controls underwent an MRI scan and clinical testing to evaluate physical disability, cognitive impairment, and apathy. In PSP, the contribution of WM tract damage to global disease severity and cognitive and behavioural disturbances was assessed using Random Forest analysis. Relative to controls, PSP patients showed diffusion tensor (DT) MRI abnormalities of the corpus callosum, superior cerebellar peduncle (SCP), cingulum and uncinate fasciculus bilaterally, and right inferior longitudinal fasciculus. Corpus callosum and SCP DT MRI measures distinguished PSP from PD patients with high accuracy (area under the curve ranging from 0.89 to 0.72). In PSP, DT MRI metrics of the corpus callosum and superior cerebellar peduncles were the best predictors of global disease severity scale scores. DT MRI metrics of the corpus callosum, right superior longitudinal and inferior longitudinal fasciculus, and left uncinate were the best predictors of executive dysfunction. In PSP, apathy severity was related to the damage to the corpus callosum, right superior longitudinal, and uncinate fasciculi. In conclusion, WM tract damage contributes to the motor, cognitive, and behavioural deficits in PSP. DT MRI offers markers for PSP diagnosis, assessment, and monitoring.

Polyethylene damage and deformation on fixed-bearing, non-conforming unicondylar knee replacements corresponding to progressive changes in alignment and fixation.

PubMed

Harman, Melinda K; Schmitt, Sabine; Rössing, Sven; Banks, Scott A; Sharf, Hans-Peter; Viceconti, Marco; Hodge, W Andrew

2010-07-01

Deviations from nominal alignment of unicondylar knee replacements impact knee biomechanics, including the load and stress distribution at the articular contact surfaces. This study characterizes relationships between the biomechanical environment, distinguished by progressive changes in alignment and fixation, and articular damage and deformation in a consecutive series of retrieved unicondylar knee replacements. Twenty seven fixed-bearing, non-conforming unicondylar knee replacements of one design were retrieved after 2 to 13 years of in vivo function. The in vivo biomechanical environment was characterized by grading component migration measured from full-length radiographs and grading component fixation based on intraoperative manual palpation. Articular damage patterns and linear deformation on the polyethylene inserts were measured using optical photogrammetry and contact point digitization. Articular damage patterns and surface deformation on the explanted polyethylene inserts corresponded to progressive changes in component alignment and fixation. Component migration produced higher deformation rates, whereas loosening contributed to larger damage areas but lower deformation rates. Migration and loosening of the femoral component, but not the tibial component, were factors contributing to large regions of abrasion concentrated on the articular periphery. Classifying component migration and fixation at revision proved useful for distinguishing common biomechanical conditions associated with the varied polyethylene damage patterns and linear deformation for this fixed-bearing, non-conforming design. Pre-clinical evaluations of unicondylar knee replacements that are capable of reproducing variations in clinical alignment and predicting the observed wear mechanisms are necessary to better understand the impact of knee biomechanics and design on unicondylar knee replacement longevity. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Factors that influence career progression among postdoctoral clinical academics: a scoping review of the literature.

PubMed

Ranieri, Veronica; Barratt, Helen; Fulop, Naomi; Rees, Geraint

2016-10-21

The future of academic medicine is uncertain. Concerns regarding the future availability of qualified and willing trainee clinical academics have been raised worldwide. Of significant concern is our failure to retain postdoctoral trainee clinical academics, who are likely to be our next generation of leaders in scientific discovery. To review the literature about factors that may influence postdoctoral career progression in early career clinical academics. This study employed a scoping review method. Three reviewers separately assessed whether the articles found fit the inclusion criteria. PubMed, Scopus, Web of Science and Google Scholar (1991-2015). The review encompassed a broad search of English language studies published anytime up to November 2015. All articles were eligible for inclusion, including research papers employing either quantitative or qualitative methods, as well as editorials and other summary articles. Data extracted from included publications were charted according to author(s), sample population, study design, key findings, country of origin and year of publication. Our review identified 6 key influences: intrinsic motivation, work-life balance, inclusiveness, work environment, mentorship and availability of funding. It also detected significant gaps within the literature about these influences. Three key steps are proposed to help support postdoctoral trainee clinical academics. These focus on ensuring that researchers feel encouraged in their workplace, involved in collaborative dialogue with key stakeholders and able to access reliable information regarding their chosen career pathway. Finally, we highlight recommendations for future research. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Clinical and electroretinographic findings of progressive retinal atrophy in miniature schnauzer dogs of South Korea.

PubMed

Jeong, Man Bok; Park, Shin Ae; Kim, Se Eun; Park, Young Woo; Narfström, Kristina; Seo, Kangmoon

2013-10-01

The purpose of the study was to describe the clinical and electroretinographic features of clinical cases of progressive retinal atrophy (PRA) in miniature schnauzer (MS) of South Korea. Sixty-six MS (14 normal and 52 affected) were included. All animals underwent routine ocular examinations. Electroretinogram (ERG) was recorded in the 14 normal and 15 affected dogs. For normal dogs, the mean age ± SD was 4.1 ± 2.4 years (1 to 9 years), and there were no ocular abnormalities on the basis of ocular examinations and ERG results. For the PRA-affected dogs, it was shown that the mean age ± SD was 4.3 ± 1.1 years (2 to 7 years), and 44 dogs (84.6%) were 3 to 5 years old. Most of the PRA-affected dogs had abnormal menace responses (98.1%) and pupillary light reflexes (PLRs, 88.5%); some dogs showed normal menace response (1.9%) and PLRs (11.5%). Ophthalmoscopic abnormalities in the affected group included one or more of the following changes: hyperreflectivity and discoloration of the tapetal area, attenuation of retinal vessels, depigmentation in non-tapetal area and optic disc atrophy. ERG in the affected dogs showed non-recordable responses in all cases tested with clinical signs of PRA. The present study showed that PRA in MS was mainly observed between the age of 3 to 5 years. ERG revealed abnormal rod and cone responses in affected dogs at the ages studied.

Clinical and Electroretinographic Findings of Progressive Retinal Atrophy in Miniature Schnauzer Dogs of South Korea

PubMed Central

JEONG, Man Bok; PARK, Shin Ae; KIM, Se Eun; PARK, Young Woo; NARFSTRÖM, Kristina; SEO, Kangmoon

2013-01-01

ABSTRACT The purpose of the study was to describe the clinical and electroretinographic features of clinical cases of progressive retinal atrophy (PRA) in miniature schnauzer (MS) of South Korea. Sixty-six MS (14 normal and 52 affected) were included. All animals underwent routine ocular examinations. Electroretinogram (ERG) was recorded in the 14 normal and 15 affected dogs. For normal dogs, the mean age ± SD was 4.1 ± 2.4 years (1 to 9 years), and there were no ocular abnormalities on the basis of ocular examinations and ERG results. For the PRA-affected dogs, it was shown that the mean age ± SD was 4.3 ± 1.1 years (2 to 7 years), and 44 dogs (84.6%) were 3 to 5 years old. Most of the PRA-affected dogs had abnormal menace responses (98.1%) and pupillary light reflexes (PLRs, 88.5%); some dogs showed normal menace response (1.9%) and PLRs (11.5%). Ophthalmoscopic abnormalities in the affected group included one or more of the following changes: hyperreflectivity and discoloration of the tapetal area, attenuation of retinal vessels, depigmentation in non-tapetal area and optic disc atrophy. ERG in the affected dogs showed non-recordable responses in all cases tested with clinical signs of PRA. The present study showed that PRA in MS was mainly observed between the age of 3 to 5 years. ERG revealed abnormal rod and cone responses in affected dogs at the ages studied. PMID:23719750

Stars and linear dunes on Mars

NASA Technical Reports Server (NTRS)

Edgett, Kenneth S.; Blumberg, Dan G.

1994-01-01

A field containing 11 star and incipient star dunes occurs on Mars at 8.8 deg S, 270.9 deg W. Examples of linear dunes are found in a crater at 59.4 deg S, 343 deg W. While rare, dune varieties that form in bi- and multidirectional wind regimes are not absent from the surface of Mars. The occurence of both of these dune fields offers new insight into the nature of martian wind conditions and sand supply. The linear dunes appears to have formed through modification of a formerly transverse aeolian deposit, suggesting a relatively recent change in local wind direction. The 11 dunes in the star dune locality show a progressive change from barchan to star form as each successive dune has traveled up into a valley, into a more complex wind regime. The star dunes corroborate the model of N. Lancaster (1989), for the formation of star dunes by projection of transverse dunes into a complex, topographically influenced wind regime. The star dunes have dark streaks emanating from them, providing evidence that the dunes were active at or near the time the relevant image was obtained by the Viking 1 orbiter in 1978. The star and linear dunes described here are located in different regions on the martian surface. Unlike most star and linear dunes on Earth, both martian examples are isolated occurrences; neither is part of a major sand sea. Previously published Mars general circulation model results suggest that the region in which the linear dune field occurs should be a bimodal wind regime, while the region in which the star dunes occur should be unimodal. The star dunes are probably the result of localized complication of the wind regime owing to topographic confinement of the dunes. Local topographic influence on wind regime is also evident in the linear dune field, as there are transverse dunes in close proximity to the linear dunes, and their occurrence is best explained by funneling of wind through a topographic gap in the upwind crater wall.

TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort.

PubMed

Molnar, Christoph; Scherer, Almut; Baraliakos, Xenofon; de Hooge, Manouk; Micheroli, Raphael; Exer, Pascale; Kissling, Rudolf O; Tamborrini, Giorgio; Wildi, Lukas M; Nissen, Michael J; Zufferey, Pascal; Bernhard, Jürg; Weber, Ulrich; Landewé, Robert B M; van der Heijde, Désirée; Ciurea, Adrian

2018-01-01

To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS). Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis. A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97). TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

PubMed

Monte, Thais Lampert; Reckziegel, Estela da Rosa; Augustin, Marina Coutinho; Locks-Coelho, Lucas D; Santos, Amanda Senna P; Furtado, Gabriel Vasata; de Mattos, Eduardo Preusser; Pedroso, José Luiz; Barsottini, Orlando Póvoas; Vargas, Fernando Regla; Saraiva-Pereira, Maria-Luiza; Camey, Suzi Alves; Leotti, Vanessa Bielefeldt; Jardim, Laura Bannach

2018-01-25

Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is

Progress of artificial pancreas devices towards clinical use: the first outpatient studies.

PubMed

Russell, Steven J

2015-04-01

This article describes recent progress in the automated control of glycemia in type 1 diabetes with artificial pancreas devices that combine continuous glucose monitoring with automated decision-making and insulin delivery. After a gestation period of closely supervised feasibility studies in research centers, the last 2 years have seen publication of studies testing these devices in outpatient environments, and many more such studies are ongoing. The most basic form of automation, suspension of insulin delivery for actual or predicted hypoglycemia, has been shown to be effective and well tolerated, and a first-generation device has actually reached the market. Artificial pancreas devices that actively dose insulin fall into two categories, those that dose insulin alone and those that also use glucagon to prevent and treat hypoglycemia (bihormonal artificial pancreas). Initial outpatient clinical trials have shown that both strategies can improve glycemic management in comparison with patient-controlled insulin pump therapy, but only the bihormonal strategy has been tested without restrictions on exercise. Artificial pancreas technology has the potential to reduce acute and chronic complications of diabetes and mitigate the burden of diabetes self-management. Successful outpatient studies bring these technologies one step closer to availability for patients.

Progressive supranuclear palsy syndrome induced by clebopride.

PubMed

Campdelacreu, Jaume; Kumru, Hatice; Tolosa, Eduard; Valls-Solé, Josep; Benabarre, Antoni

2004-04-01

We report on a patient who presented with a progressive supranuclear palsy (PSP) syndrome while receiving clebopride (CLB), a prokinetic drug with central antidopaminergic properties. The clinical and neurophysiological signs progressively disappeared after CLB withdrawal. To our knowledge, this is the first published PSP-like syndrome attributable to an antidopaminergic drug. Copyright 2003 Movement Disorder Society

Beta-Zone parapapillary atrophy and the velocity of glaucoma progression.

PubMed

Teng, Christopher C; De Moraes, Carlos Gustavo V; Prata, Tiago S; Tello, Celso; Ritch, Robert; Liebmann, Jeffrey M

2010-05-01

Beta-Zone parapapillary atrophy (PPA) occurs more commonly in eyes with glaucoma. Rates of glaucomatous visual field (VF) progression in eyes with and without beta-zone PPA at the time of baseline assessment were compared. Retrospective, comparative study. Two hundred forty-five patients from the New York Glaucoma Progression Study. Subjects with glaucomatous optic neuropathy and repeatable VF loss were assessed for eligibility. Eyes with a Heidelberg Retina Tomograph II (HRT) examination, at least 5 visual field tests after the HRT in either eye, optic disc photographs, and <6 diopters of myopia were enrolled. beta-Zone PPA was defined as a region of chorioretinal atrophy with visible sclera and choroidal vessels adjacent to the optic disc. Global rates of VF progression were determined by automated pointwise linear regression analysis. Univariate analysis included age, gender, ethnicity, central corneal thickness (CCT), refractive error, baseline mean deviation, baseline intraocular pressure (IOP), mean IOP, IOP fluctuation, disc area, rim area, rim area-to-disc area ratio, beta-zone PPA area, beta-zone PPA area-to-disc area ratio, and presence or absence of beta-zone PPA. The relationship between beta-zone PPA and the rate and risk of glaucoma progression. Two hundred forty-five eyes of 245 patients (mean age, 69.6+/-12.3 years) were enrolled. The mean follow-up was 4.9+/-1.4 years and the mean number of VFs after HRT was 9.3+/-2.7. beta-Zone PPA was present in 146 eyes (65%). Eyes with beta-zone PPA progressed more rapidly (-0.84+/-0.8 dB/year) than eyes without it (-0.51+/-0.6 dB/year; P<0.01). Multivariate regression showed significant influence of mean IOP (hazard ratio [HR], 1.11; P<0.01), IOP fluctuation (HR, 1.17; P = 0.02), and presence of beta-zone PPA (HR, 2.59; P<0.01) on VF progression. Moderate (0.5-1.5 dB/year; P = 0.01) and fast (>1.5 dB/year; P = 0.08) global rates of progression occurred more commonly in eyes with beta-zone PPA than in eyes

Comparison of Linear and Non-linear Regression Analysis to Determine Pulmonary Pressure in Hyperthyroidism.

PubMed

Scarneciu, Camelia C; Sangeorzan, Livia; Rus, Horatiu; Scarneciu, Vlad D; Varciu, Mihai S; Andreescu, Oana; Scarneciu, Ioan

2017-01-01

This study aimed at assessing the incidence of pulmonary hypertension (PH) at newly diagnosed hyperthyroid patients and at finding a simple model showing the complex functional relation between pulmonary hypertension in hyperthyroidism and the factors causing it. The 53 hyperthyroid patients (H-group) were evaluated mainly by using an echocardiographical method and compared with 35 euthyroid (E-group) and 25 healthy people (C-group). In order to identify the factors causing pulmonary hypertension the statistical method of comparing the values of arithmetical means is used. The functional relation between the two random variables (PAPs and each of the factors determining it within our research study) can be expressed by linear or non-linear function. By applying the linear regression method described by a first-degree equation the line of regression (linear model) has been determined; by applying the non-linear regression method described by a second degree equation, a parabola-type curve of regression (non-linear or polynomial model) has been determined. We made the comparison and the validation of these two models by calculating the determination coefficient (criterion 1), the comparison of residuals (criterion 2), application of AIC criterion (criterion 3) and use of F-test (criterion 4). From the H-group, 47% have pulmonary hypertension completely reversible when obtaining euthyroidism. The factors causing pulmonary hypertension were identified: previously known- level of free thyroxin, pulmonary vascular resistance, cardiac output; new factors identified in this study- pretreatment period, age, systolic blood pressure. According to the four criteria and to the clinical judgment, we consider that the polynomial model (graphically parabola- type) is better than the linear one. The better model showing the functional relation between the pulmonary hypertension in hyperthyroidism and the factors identified in this study is given by a polynomial equation of second

Using dreams to assess clinical change during treatment.

PubMed

Glucksman, Myron L; Kramer, Milton

2004-01-01

This article describes several studies that examine the relationship between the manifest content of selected dreams reported by patients and their clinical progress during psychoanalytic and psychodynamically oriented treatment. There are a number of elements that dreaming and psychotherapy have in common: affect regulation; conflict resolution; problem-solving; self-awareness; mastery and adaptation. Four different studies examined the relationship between the manifest content of selected dreams and clinical progress during treatment. In each study, the ratings of manifest content and clinical progress by independent observers were rank-ordered and compared. In three of the four studies there was a significant correlation between the rankings of manifest content and the rankings of clinical progress. This finding suggests that the manifest content of dreams can be used as an independent variable to assess clinical progress during psychoanalytic and psychodynamically oriented treatment.

Longitudinal trajectory of clinical insight and covariation with cortical thickness in first-episode psychosis.

PubMed

Buchy, Lisa; Makowski, Carolina; Malla, Ashok; Joober, Ridha; Lepage, Martin

2017-03-01

Among people with a first-episode of psychosis, those with poorer clinical insight show neuroanatomical abnormalities in frontal, temporal and parietal cortices compared to those with better clinical insight. Whether changes in clinical insight are associated with progressive structural brain changes is unknown. We aimed to evaluate 1) associations between clinical insight and cortical thickness at a baseline assessment, 2) covariation between clinical insight and cortical thickness across baseline, one-year and two-year follow-up assessments, and 3) the predictive value of clinical insight for cortical thickness at one-year and two-year follow-ups. Scale for the assessment of Unawareness of Mental Disorder ratings and magnetic resonance imaging scans were acquired at baseline, one-year, and two-year follow-ups in 128, 74, and 44 individuals with a first-episode psychosis, respectively. Cortical thickness metrics were then computed at baseline, one-year and two-year follow-ups and analyzed with linear mixed models. At baseline, clinical insight was not significantly associated with cortical thickness in any region. Longitudinal mixed effects models showed that a worsening in clinical insight between the one-year and two-year assessments was significantly associated with cortical thinning in dorsal pre-central and post-central gyri. Cortical thinning in left fusiform gyrus at two-years was predicted by poorer clinical insight at baseline. Results suggest that poor clinical insight soon after the onset of a first-episode psychosis may lead to progressive cortical changes in temporal lobe, while changes in clinical insight during the second year covary with cortical thinning in circumscribed dorsal frontal and parietal cortices. Copyright © 2016 Elsevier Ltd. All rights reserved.

Series length used during trend analysis affects sensitivity to changes in progression rate in the ocular hypertension treatment study.

PubMed

Gardiner, Stuart K; Demirel, Shaban; De Moraes, Carlos Gustavo; Liebmann, Jeffrey M; Cioffi, George A; Ritch, Robert; Gordon, Mae O; Kass, Michael A

2013-02-15

Trend analysis techniques to detect glaucomatous progression typically assume a constant rate of change. This study uses data from the Ocular Hypertension Treatment Study to assess whether this assumption decreases sensitivity to changes in progression rate, by including earlier periods of stability. Series of visual fields (mean 24 per eye) completed at 6-month intervals from participants randomized initially to observation were split into subseries before and after the initiation of treatment (the "split-point"). The mean deviation rate of change (MDR) was derived using these entire subseries, and using only the window length (W) tests nearest the split-point, for different window lengths of W tests. A generalized estimating equation model was used to detect changes in MDR occurring at the split-point. Using shortened subseries with W = 7 tests, the MDR slowed by 0.142 dB/y upon initiation of treatment (P < 0.001), and the proportion of eyes showing "rapid deterioration" (MDR <-0.5 dB/y with P < 5%) decreased from 11.8% to 6.5% (P < 0.001). Using the entire sequence, no significant change in MDR was detected (P = 0.796), and there was no change in the proportion of eyes progressing (P = 0.084). Window lengths 6 ≤ W ≤ 9 produced similar benefits. Event analysis revealed a beneficial treatment effect in this dataset. This effect was not detected by linear trend analysis applied to entire series, but was detected when using shorter subseries of length between six and nine fields. Using linear trend analysis on the entire field sequence may not be optimal for detecting and monitoring progression. Nonlinear analyses may be needed for long series of fields. (ClinicalTrials.gov number, NCT00000125.).

Linear and nonlinear regression techniques for simultaneous and proportional myoelectric control.

PubMed

Hahne, J M; Biessmann, F; Jiang, N; Rehbaum, H; Farina, D; Meinecke, F C; Muller, K-R; Parra, L C

2014-03-01

In recent years the number of active controllable joints in electrically powered hand-prostheses has increased significantly. However, the control strategies for these devices in current clinical use are inadequate as they require separate and sequential control of each degree-of-freedom (DoF). In this study we systematically compare linear and nonlinear regression techniques for an independent, simultaneous and proportional myoelectric control of wrist movements with two DoF. These techniques include linear regression, mixture of linear experts (ME), multilayer-perceptron, and kernel ridge regression (KRR). They are investigated offline with electro-myographic signals acquired from ten able-bodied subjects and one person with congenital upper limb deficiency. The control accuracy is reported as a function of the number of electrodes and the amount and diversity of training data providing guidance for the requirements in clinical practice. The results showed that KRR, a nonparametric statistical learning method, outperformed the other methods. However, simple transformations in the feature space could linearize the problem, so that linear models could achieve similar performance as KRR at much lower computational costs. Especially ME, a physiologically inspired extension of linear regression represents a promising candidate for the next generation of prosthetic devices.

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.

PubMed

Kridel, Robert; Chan, Fong Chun; Mottok, Anja; Boyle, Merrill; Farinha, Pedro; Tan, King; Meissner, Barbara; Bashashati, Ali; McPherson, Andrew; Roth, Andrew; Shumansky, Karey; Yap, Damian; Ben-Neriah, Susana; Rosner, Jamie; Smith, Maia A; Nielsen, Cydney; Giné, Eva; Telenius, Adele; Ennishi, Daisuke; Mungall, Andrew; Moore, Richard; Morin, Ryan D; Johnson, Nathalie A; Sehn, Laurie H; Tousseyn, Thomas; Dogan, Ahmet; Connors, Joseph M; Scott, David W; Steidl, Christian; Marra, Marco A; Gascoyne, Randy D; Shah, Sohrab P

2016-12-01

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

PubMed Central

Mottok, Anja; Boyle, Merrill; Tan, King; Meissner, Barbara; Bashashati, Ali; Roth, Andrew; Shumansky, Karey; Nielsen, Cydney; Giné, Eva; Moore, Richard; Morin, Ryan D.; Sehn, Laurie H.; Tousseyn, Thomas; Dogan, Ahmet; Scott, David W.; Steidl, Christian; Gascoyne, Randy D.; Shah, Sohrab P.

2016-01-01

Background Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Methods and Findings Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2

Rethinking Clinical Workflow.

PubMed

Schlesinger, Joseph J; Burdick, Kendall; Baum, Sarah; Bellomy, Melissa; Mueller, Dorothee; MacDonald, Alistair; Chern, Alex; Chrouser, Kristin; Burger, Christie

2018-03-01

The concept of clinical workflow borrows from management and leadership principles outside of medicine. The only way to rethink clinical workflow is to understand the neuroscience principles that underlie attention and vigilance. With any implementation to improve practice, there are human factors that can promote or impede progress. Modulating the environment and working as a team to take care of patients is paramount. Clinicians must continually rethink clinical workflow, evaluate progress, and understand that other industries have something to offer. Then, novel approaches can be implemented to take the best care of patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Crevicular Fluid Biomarkers and Periodontal Disease Progression

PubMed Central

Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

2014-01-01

Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

Linear data mining the Wichita clinical matrix suggests sleep and allostatic load involvement in chronic fatigue syndrome.

PubMed

Gurbaxani, Brian M; Jones, James F; Goertzel, Benjamin N; Maloney, Elizabeth M

2006-04-01

To provide a mathematical introduction to the Wichita (KS, USA) clinical dataset, which is all of the nongenetic data (no microarray or single nucleotide polymorphism data) from the 2-day clinical evaluation, and show the preliminary findings and limitations, of popular, matrix algebra-based data mining techniques. An initial matrix of 440 variables by 227 human subjects was reduced to 183 variables by 164 subjects. Variables were excluded that strongly correlated with chronic fatigue syndrome (CFS) case classification by design (for example, the multidimensional fatigue inventory [MFI] data), that were otherwise self reporting in nature and also tended to correlate strongly with CFS classification, or were sparse or nonvarying between case and control. Subjects were excluded if they did not clearly fall into well-defined CFS classifications, had comorbid depression with melancholic features, or other medical or psychiatric exclusions. The popular data mining techniques, principle components analysis (PCA) and linear discriminant analysis (LDA), were used to determine how well the data separated into groups. Two different feature selection methods helped identify the most discriminating parameters. Although purely biological features (variables) were found to separate CFS cases from controls, including many allostatic load and sleep-related variables, most parameters were not statistically significant individually. However, biological correlates of CFS, such as heart rate and heart rate variability, require further investigation. Feature selection of a limited number of variables from the purely biological dataset produced better separation between groups than a PCA of the entire dataset. Feature selection highlighted the importance of many of the allostatic load variables studied in more detail by Maloney and colleagues in this issue [1] , as well as some sleep-related variables. Nonetheless, matrix linear algebra-based data mining approaches appeared to be of

The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.

PubMed

Cottrell, D A; Kremenchutzky, M; Rice, G P; Koopman, W J; Hader, W; Baskerville, J; Ebers, G C

1999-04-01

We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural

Risk Factors for Primary Open Angle Glaucoma (POAG) Progression: A Study Ruled in Torino

PubMed Central

Actis, A.G.; Versino, E.; Brogliatti, B.; Rolle, T.

2016-01-01

Purpose: Aim of this retrospective, observational study is to describe features of a population sample, affected by primary open angle glaucoma (POAG) in order to evaluate damage progression on the basis of the emerged individual risk factors. Methods: We included 190 caucasian patients (377 eyes), evaluating relationship between individual risk factors (explicative variables) and MD (Mean Deviation) of standard automated perimetry. We also considered the dependent variable NFI (Neural Fiber Index) of GDx scanning laser polarimetry. Progression has been evaluated through a statistic General Linear Model on four follow up steps (mean follow up 79 months). Results: Factors reaching statistical significance, determining a worsening of the MD variable, are: age (P<0.0001), intraocular pressure (IOP) at follow up (P < 0.0001), female gender (P<0.0001), hypertension (P< 0.0001) and familiarity (P = 0.0006). Factors reaching statistical significance, determining a worsening of the NFI variable, are only IOP at follow up (P = 0.0159) and depression (P = 0.0104). Conclusion: Results of this study confirm and enforce data coming from most recent studies: IOP remains the main risk factor for glaucoma assess and progression; age and familiarity are great risk factors as underlined in the last decades; female sex can be an important risk factors as emerged only in the last years; arterial hypertension should always be evaluated in timing of our clinic follow up. PMID:27347249

Using linear programming to minimize the cost of nurse personnel.

PubMed

Matthews, Charles H

2005-01-01

Nursing personnel costs make up a major portion of most hospital budgets. This report evaluates and optimizes the utility of the nurse personnel at the Internal Medicine Outpatient Clinic of Wake Forest University Baptist Medical Center. Linear programming (LP) was employed to determine the effective combination of nurses that would allow for all weekly clinic tasks to be covered while providing the lowest possible cost to the department. Linear programming is a standard application of standard spreadsheet software that allows the operator to establish the variables to be optimized and then requires the operator to enter a series of constraints that will each have an impact on the ultimate outcome. The application is therefore able to quantify and stratify the nurses necessary to execute the tasks. With the report, a specific sensitivity analysis can be performed to assess just how sensitive the outcome is to the stress of adding or deleting a nurse to or from the payroll. The nurse employee cost structure in this study consisted of five certified nurse assistants (CNA), three licensed practicing nurses (LPN), and five registered nurses (RN). The LP revealed that the outpatient clinic should staff four RNs, three LPNs, and four CNAs with 95 percent confidence of covering nurse demand on the floor. This combination of nurses would enable the clinic to: 1. Reduce annual staffing costs by 16 percent; 2. Force each level of nurse to be optimally productive by focusing on tasks specific to their expertise; 3. Assign accountability more efficiently as the nurses adhere to their specific duties; and 4. Ultimately provide a competitive advantage to the clinic as it relates to nurse employee and patient satisfaction. Linear programming can be used to solve capacity problems for just about any staffing situation, provided the model is indeed linear.

A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.

PubMed

André, F E; Foulkes, M A

1998-01-01

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production

Progressive transmission of road network

NASA Astrophysics Data System (ADS)

Ai, Bo; Ai, Tinghua; Tang, Xinming; Li, Zhen

2009-10-01

The progressive transmission of vector map data requires efficient multi-scale data model to process the data into hierarchical structure. This paper presents such a data structure of road network without redundancy of geometry for progressive transmission. For a given scale, the road network display has to settle two questions. One is which road objects to be represented and the other is what geometric details to be visualized for the selected roads. This paper combines the Töpfer law and the BLG-tree structure into a multi-scale representation matrix to answer simultaneously the above two questions. In the matrix, rows from top to bottom represent the roads in the sequence of descending classification of traffic and length, which can support the Töpfer law to retrieve the more important roads. In a row, columns record one road by a linear BLG-tree to provide good line graphics.

Clinical Investigation Program Annual Progress Report

DTIC Science & Technology

1989-10-01

Investigators: Linda K. Kullama, Ph.D., Dr. Kenneth T. Nakamura,MD; Dr. Venkataraman Balaraman, MD, Wayne M. Ichimura, Biomedical Engineer. Department/Section...Investigators: John R. Claybaugh, Ph.D.; Kenneth T. Nakamura, MD; Dr. Venkataraman Balaraman, M.D. Department/Section: Clinical Investigation/Physiology Key...Pigs and Rats Principal ’Investigator: Linda K. Kullama, Ph.D.; John R. Claybaugh, Ph.D. Associate Investigators: Dr. Venkataraman Balaraman, M.D.; Dr

Clinical Investigation Program Annual Progress Report

DTIC Science & Technology

1989-09-30

initiatives for the study of relatedness of bacterial and HLA antigens as they influence autoimmune diseases. Microbiology Service - FY 89 An in-house...1030 87/103 0 Identification of Those at Risk for Osteoporotic Hip Fractures, by an Noninvasive Measurement (P) (PR)... 105 87/104 0 SWOG 8600 - A...233 82/302 0 The Evaluation of Recently Introduced, Commercially Available Clinical Microbiology Products for Possible

Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease

PubMed Central

2015-01-01

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5–4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95

Trajectories of impairment in amyotrophic lateral sclerosis: Insights from the Pooled Resource Open-Access ALS Clinical Trials cohort.

PubMed

Thakore, Nimish J; Lapin, Brittany R; Pioro, Erik P

2018-06-01

Rate of decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score is a common outcome measure and a powerful predictor of mortality in ALS. Observed rate of decline (postslope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (preslope) were examined in the Pooled Resource Open-Access ALS Clinical Trials cohort by using longitudinal mixed effects models. Mean ALSFRS-R postslope in 3,367 patients was -0.99 points/month. Preslope and postslope were correlated and had powerful effects on survival. ALSFRS-R trajectories were slightly accelerated overall, but slope and direction/degree of curvature varied. Subscore decline was sequential by site of onset. Respiratory subscore decline was the least steep. Variable curvilinearity of ALSFRS-R trajectories confounds interpretation in clinical studies that assume linear decline. Subscore trajectories recapitulate phenotypic diversity and topographical progression of ALS. ALSFRS-R is better used as a multidimensional measure. Muscle Nerve 57: 937-945, 2018. © 2017 Wiley Periodicals, Inc.

An evolutive real-time source inversion based on a linear inverse formulation

NASA Astrophysics Data System (ADS)

Sanchez Reyes, H. S.; Tago, J.; Cruz-Atienza, V. M.; Metivier, L.; Contreras Zazueta, M. A.; Virieux, J.

2016-12-01

Finite source inversion is a steppingstone to unveil earthquake rupture. It is used on ground motion predictions and its results shed light on seismic cycle for better tectonic understanding. It is not yet used for quasi-real-time analysis. Nowadays, significant progress has been made on approaches regarding earthquake imaging, thanks to new data acquisition and methodological advances. However, most of these techniques are posterior procedures once seismograms are available. Incorporating source parameters estimation into early warning systems would require to update the source build-up while recording data. In order to go toward this dynamic estimation, we developed a kinematic source inversion formulated in the time-domain, for which seismograms are linearly related to the slip distribution on the fault through convolutions with Green's functions previously estimated and stored (Perton et al., 2016). These convolutions are performed in the time-domain as we progressively increase the time window of records at each station specifically. Selected unknowns are the spatio-temporal slip-rate distribution to keep the linearity of the forward problem with respect to unknowns, as promoted by Fan and Shearer (2014). Through the spatial extension of the expected rupture zone, we progressively build-up the slip-rate when adding new data by assuming rupture causality. This formulation is based on the adjoint-state method for efficiency (Plessix, 2006). The inverse problem is non-unique and, in most cases, underdetermined. While standard regularization terms are used for stabilizing the inversion, we avoid strategies based on parameter reduction leading to an unwanted non-linear relationship between parameters and seismograms for our progressive build-up. Rise time, rupture velocity and other quantities can be extracted later on as attributs from the slip-rate inversion we perform. Satisfactory results are obtained on a synthetic example (FIgure 1) proposed by the Source

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

PubMed

Wang, S; Martinez-Lage, M; Sakai, Y; Chawla, S; Kim, S G; Alonso-Basanta, M; Lustig, R A; Brem, S; Mohan, S; Wolf, R L; Desai, A; Poptani, H

2016-01-01

Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from

Deep brain stimulation of the pedunculopontine nucleus for treatment of gait and balance disorder in progressive supranuclear palsy: Effects of frequency modulations and clinical outcome.

PubMed

Galazky, Imke; Kaufmann, Jörn; Lorenzl, Stefan; Ebersbach, Georg; Gandor, Florin; Zaehle, Tino; Specht, Sylke; Stallforth, Sabine; Sobieray, Uwe; Wirkus, Edyta; Casjens, Franziska; Heinze, Hans-Jochen; Kupsch, Andreas; Voges, Jürgen

2018-05-01

The pedunculopontine nucleus has been suggested as a potential deep brain stimulation target for axial symptoms such as gait and balance impairment in idiopathic Parkinson's disease as well as atypical Parkinsonian disorders. Seven consecutive patients with progressive supranuclear palsy received bilateral pedunculopontine nucleus deep brain stimulation. Inclusion criteria comprised of the clinical diagnosis of progressive supranuclear palsy, a levodopa-resistant gait and balance disorder, age <75 years, and absence of dementia or major psychiatric co-morbidities. Effects of stimulation frequencies at 8, 20, 60 and 130 Hz on motor scores and gait were assessed. Motor scores were followed up for two years postoperatively. Activities of daily living, frequency of falls, health-related quality of life, cognition and mood at 12 months were compared to baseline parameters. Surgical and stimulation related adverse events were assessed. Bilateral pedunculopontine nucleus deep brain stimulation at 8 Hz significantly improved axial motor symptoms and cyclic gait parameters, while high frequency stimulation did not ameliorate gait and balance but improved hypokinesia. This improvement however did not translate into clinically relevant benefits. Frequency of falls was not reduced. Activities of daily living, quality of life and frontal cognitive functions declined, while mood remained unchanged. Bilateral pedunculopontine nucleus deep brain stimulation in progressive supranuclear palsy generates frequency-dependent effects with improvement of cyclic gait parameters at low frequency and amelioration of hypokinesia at high frequency stimulation. However, these effects do not translate into a clinically important improvement. Copyright © 2018. Published by Elsevier Ltd.

Advancing functional dysconnectivity and atrophy in progressive supranuclear palsy.

PubMed

Brown, Jesse A; Hua, Alice Y; Trujllo, Andrew; Attygalle, Suneth; Binney, Richard J; Spina, Salvatore; Lee, Suzee E; Kramer, Joel H; Miller, Bruce L; Rosen, Howard J; Boxer, Adam L; Seeley, William W

2017-01-01

Progressive supranuclear palsy syndrome (PSP-S) results from neurodegeneration within a network of brainstem, subcortical, frontal and parietal cortical brain regions. It is unclear how network dysfunction progresses and relates to longitudinal atrophy and clinical decline. In this study, we evaluated patients with PSP-S (n = 12) and healthy control subjects (n = 20) at baseline and 6 months later. Subjects underwent structural MRI and task-free functional MRI (tf-fMRI) scans and clinical evaluations at both time points. At baseline, voxel based morphometry (VBM) revealed that patients with mild-to-moderate clinical symptoms showed structural atrophy in subcortex and brainstem, prefrontal cortex (PFC; supplementary motor area, paracingulate, dorsal and ventral medial PFC), and parietal cortex (precuneus). Tf-fMRI functional connectivity (FC) was examined in a rostral midbrain tegmentum (rMT)-anchored intrinsic connectivity network that is compromised in PSP-S. In healthy controls, this network contained a medial parietal module, a prefrontal-paralimbic module, and a subcortical-brainstem module. Baseline FC deficits in PSP-S were most severe in rMT network integrative hubs in the prefrontal-paralimbic and subcortical-brainstem modules. Longitudinally, patients with PSP-S had declining intermodular FC between the subcortical-brainstem and parietal modules, while progressive atrophy was observed in subcortical-brainstem regions (midbrain, pallidum) and posterior frontal (perirolandic) cortex. This suggested that later-stage subcortical-posterior cortical change may follow an earlier-stage subcortical-anterior cortical disease process. Clinically, patients with more severe baseline impairment showed greater subsequent prefrontal-parietal cortical FC declines and posterior frontal atrophy rates, while patients with more rapid longitudinal clinical decline showed coupled prefrontal-paralimbic FC decline. VBM and FC can augment disease monitoring in PSP-S by

Lack of clinical and histological progression of chronic hepatitis C in individuals with true persistently normal ALT: the result of a 17-year follow-up.

PubMed

Nunnari, G; Pinzone, M R; Cacopardo, B

2013-04-01

Thirty to 40% of patients with chronic hepatitis C have persistently normal alanine aminotransferase (PNALT). Even though traditionally considered as healthy people, most PNALT carriers actually have some degree of clinical progression and histological liver damage. We evaluated the clinical and histological outcome of a 17-year follow-up on a cohort of patients with chronic HCV infection and PNALT. Between 1994 and 2011, 70 PNALTs and 55 Hyper-alanine aminotransferase (ALT) subjects underwent a clinical, biochemical, virological and histological follow-up. At the end of the follow-up, all patients were alive. In the PNALT group, none of the patients developed hepatic decompensation, while 14.5% of Hyper-ALTs were diagnosed as affected by decompensated cirrhosis. No significant variation of the Metavir grading and staging scores was observed among PNALTs by comparing pre- and post-follow-up liver specimens. On the contrary, a significant increase in both Metavir grading and staging scores was noticed within the Hyper-ALT group. Finally, the analysis of IL28B single-nucleotide polymorphism rs12979860 revealed no difference between Hyper-ALTs and PNALTs in terms of frequency of C/C genotype. In conclusion, progression of chronic hepatitis C among PNALTs is slow or even absent, because at the end of the 17-year follow-up histological and clinical parameters had not worsened significantly. © 2012 Blackwell Publishing Ltd.

Determination of lactic acid level in systemic liquids in children with progressive encephalopathies.

PubMed

Marszał, Elzbieta; Wojaczyńska-Stanek, Katarzyna; Pietruszewski, Jerzy; Emich-Widera, Ewa; Bielińska-Bujniewicz, Eugenia

2002-03-01

This article reports the results of research into the activities of lactic acid concentrations in the body fluids of children with progressive encephalopathies (PE) in comparison to patients with non-progressive encephalopathies (NPE) and those with non-progressive encephalopathies with concomitant epilepsy (NPEE). The study was designed to determine whether there is difference between the serum and CSF lactic acid concentrations in children with progressive encephalopathies (PE), static (non-progressive) encephalopathies (NPE) and non progressive encephalopathies with concomitant epilepsy (NPEE), and whether the clinical status correlates with the concentration of these biochemical markers in children with PE. The assessment involved 138 children of both sexes, whose age ranged between 8 months and 15 years, diagnosed and treated in the Neurology Department at the Pediatric Clinic of the Silesian Medical Academy in Katowice between 1995 and 1997. Lactate concentrations were determined in serum and cerebro-spinal fluid and analyzed statistically. The findings showed higher serum and CSF concentrations in children with PE than in patients who manifested non-progressive forms of encephalopathy. The degree of clinical symptom aggravation in PE children was likewise analyzed and compared to the values of lactate concentrations in body fluids; however, no correlation was found between these parameters. Children with progressive encephalopathies present higher lactate concentrations in serum and cerebrospinal fluid than patients with static (non-progressive) encephalopathy.

Asymmetry of cortical decline in subtypes of primary progressive aphasia.

PubMed

Rogalski, Emily; Cobia, Derin; Martersteck, Adam; Rademaker, Alfred; Wieneke, Christina; Weintraub, Sandra; Mesulam, M-Marsel

2014-09-23

The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials. Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes. Whole-brain vertex-wise and ROI imaging analysis were conducted using the FreeSurfer longitudinal pipeline. Clinical deficits and cortical atrophy patterns showed distinct patterns of change among the subtypes over 2 years. Results confirmed that progression for each of the 3 subtypes showed left greater than right hemisphere asymmetry. An ROI analysis also revealed that progression was greater within, rather than outside, the language network. Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA. © 2014 American Academy of Neurology.

Asymmetry of cortical decline in subtypes of primary progressive aphasia

PubMed Central

Cobia, Derin; Martersteck, Adam; Rademaker, Alfred; Wieneke, Christina; Weintraub, Sandra; Mesulam, M.-Marsel

2014-01-01

Objective: The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials. Methods: Changes in cortical thickness and volume loss as well as neuropsychological performance were assessed at baseline and 2-year follow-up in 26 patients who fulfilled criteria for logopenic (8 patients), agrammatic (10 patients), and semantic (8 patients) PPA subtypes. Whole-brain vertex-wise and ROI imaging analysis were conducted using the FreeSurfer longitudinal pipeline. Results: Clinical deficits and cortical atrophy patterns showed distinct patterns of change among the subtypes over 2 years. Results confirmed that progression for each of the 3 subtypes showed left greater than right hemisphere asymmetry. An ROI analysis also revealed that progression was greater within, rather than outside, the language network. Conclusions: Preferential neurodegeneration of the left hemisphere language network is a common denominator for all 3 PPA subtypes, even as the disease progresses. Using a focal cortical language network ROI as an outcome measure of disease progression appears to be more sensitive than whole-brain or ventricular volume measures of change and may be helpful for designing future clinical trials in PPA. PMID:25165386

Crevicular fluid biomarkers and periodontal disease progression.

PubMed

Kinney, Janet S; Morelli, Thiago; Oh, Min; Braun, Thomas M; Ramseier, Christoph A; Sugai, Jim V; Giannobile, William V

2014-02-01

Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6 months, patients received periodontal therapy and continued participation from 6 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p = 0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61, 86). Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Emphysema Distribution and Diffusion Capacity Predict Emphysema Progression in Human Immunodeficiency Virus Infection

PubMed Central

Leung, Janice M; Malagoli, Andrea; Santoro, Antonella; Besutti, Giulia; Ligabue, Guido; Scaglioni, Riccardo; Dai, Darlene; Hague, Cameron; Leipsic, Jonathon; Sin, Don D.; Man, SF Paul; Guaraldi, Giovanni

2016-01-01

Background Chronic obstructive pulmonary disease (COPD) and emphysema are common amongst patients with human immunodeficiency virus (HIV). We sought to determine the clinical factors that are associated with emphysema progression in HIV. Methods 345 HIV-infected patients enrolled in an outpatient HIV metabolic clinic with ≥2 chest computed tomography scans made up the study cohort. Images were qualitatively scored for emphysema based on percentage involvement of the lung. Emphysema progression was defined as any increase in emphysema score over the study period. Univariate analyses of clinical, respiratory, and laboratory data, as well as multivariable logistic regression models, were performed to determine clinical features significantly associated with emphysema progression. Results 17.4% of the cohort were emphysema progressors. Emphysema progression was most strongly associated with having a low baseline diffusion capacity of carbon monoxide (DLCO) and having combination centrilobular and paraseptal emphysema distribution. In adjusted models, the odds ratio (OR) for emphysema progression for every 10% increase in DLCO percent predicted was 0.58 (95% confidence interval [CI] 0.41–0.81). The equivalent OR (95% CI) for centrilobular and paraseptal emphysema distribution was 10.60 (2.93–48.98). Together, these variables had an area under the curve (AUC) statistic of 0.85 for predicting emphysema progression. This was an improvement over the performance of spirometry (forced expiratory volume in 1 second to forced vital capacity ratio), which predicted emphysema progression with an AUC of only 0.65. Conclusion Combined paraseptal and centrilobular emphysema distribution and low DLCO could identify HIV patients who may experience emphysema progression. PMID:27902753

Clinical Preceptors' Perspectives on Clinical Education in Post-Professional Athletic Training Education Programs

ERIC Educational Resources Information Center

Phan, Kelvin; McCarty, Cailee W.; Mutchler, Jessica M.; Van Lunen, Bonnie

2012-01-01

Context: Clinical education is the interaction between a clinical preceptor and student within the clinical setting to help the student progress as a clinician. Post-professional athletic training clinical education is especially important to improve these students' clinical knowledge and skills. However, little research has been conducted to…

Modeling Diverse Pathways to Age Progressive Volcanism in Subduction Zones.

NASA Astrophysics Data System (ADS)

Kincaid, C. R.; Szwaja, S.; Sylvia, R. T.; Druken, K. A.

2015-12-01

One of the best, and most challenging clues to unraveling mantle circulation patterns in subduction zones comes in the form of age progressive volcanic and geochemical trends. Hard fought geological data from many subduction zones, like Tonga-Lau, the Cascades and Costa-Rica/Nicaragua, reveal striking temporal patterns used in defining mantle flow directions and rates. We summarize results from laboratory subduction models showing a range in circulation and thermal-chemical transport processes. These interaction styles are capable of producing such trends, often reflecting apparent instead of actual mantle velocities. Lab experiments use a glucose working fluid to represent Earth's upper mantle and kinematically driven plates to produce a range in slab sinking and related wedge transport patterns. Kinematic forcing assumes most of the super-adiabatic temperature gradient available to drive major downwellings is in the tabular slabs. Moreover, sinking styles for fully dynamic subduction depend on many complicating factors that are only poorly understood and which can vary widely even for repeated parameter combinations. Kinematic models have the benefit of precise, repeatable control of slab motions and wedge flow responses. Results generated with these techniques show the evolution of near-surface thermal-chemical-rheological heterogeneities leads to age progressive surface expressions in a variety of ways. One set of experiments shows that rollback and back-arc extension combine to produce distinct modes of linear, age progressive melt delivery to the surface through a) erosion of the rheological boundary layer beneath the overriding plate, and deformation and redistribution of both b) mantle residuum produced from decompression melting and c) formerly active, buoyant plumes. Additional experiments consider buoyant diapirs rising in a wedge under the influence of rollback, back-arc spreading and slab-gaps. Strongly deflected diapirs, experiencing variable rise

Research progress on bladder cancer molecular genetics.

PubMed

Kang, Zhengjun; Li, Yuhui; Yu, Yang; Guo, Zhan

2014-11-01

Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, which threats human health. With the research on bladder cancer molecular genetics, the knowledge of gene modification and the development of molecular detection methods, more tumor markers have been discovered, which may have potential for early diagnosis, clinical examination and prognosis. This article reviews the research progress on bladder cancer molecular genetics.

Chronic progressive lymphoedema in draught horses.

PubMed

de Keyser, K; Janssens, S; Buys, N

2015-05-01

The objective of this review was to summarise and evaluate the current state of knowledge about chronic progressive lymphoedema in draught horses. Clinical signs of this multifactorial disorder are mainly restricted to the lower limbs, comprising progressively deteriorating skin, swelling and deformation. Although typical lesions were first reported at the beginning of the 20th century, chronic progressive lymphoedema was recognised as a specific syndrome only in 2003, and since then research has driven forward. Despite the high prevalence in some breeds and the serious economic impact, the pathogenesis is not fully understood, and the available treatment options remain symptomatic and noncurative. There is a need to improve diagnostic techniques and to develop selection tools. © 2014 EVJ Ltd.

Real-world usage and clinical outcomes of alectinib among post-crizotinib progression anaplastic lymphoma kinase positive non-small-cell lung cancer patients in the USA.

PubMed

DiBonaventura, Marco D; Wong, William; Shah-Manek, Bijal; Schulz, Mathias

2018-01-01

Alectinib is an approved treatment for anaplastic lymphoma kinase (ALK)-positive patients with advanced non-small-cell lung cancer. Despite positive supporting clinical data, there is a lack of real-world information on the usage and patient outcomes of those treated with alectinib post-crizotinib progression. Participating oncologists (N=95) in the USA were recruited from an online physician panel to participate in a retrospective patient chart review. Physicians randomly selected eligible patients (ie, patients who progressed on crizotinib as their first ALK inhibitor and were treated with alectinib as their second ALK inhibitor), collected demographics and clinical history from their medical charts, and entered the data into an online data collection form. A total of N=207 patient charts were included (age: 60.1±10.4 years; 53.6% male). The patients in our sample were older (median age of 60 vs 53 years), were more likely to be current smokers (12% vs 1%), had better performance status (45% vs 33% had an Eastern Cooperative Oncology Group [ECOG] of 0), and were less likely to have an adenocarcinoma histology (83% vs 96%) relative to published clinical trials. The objective response rate was higher than in clinical trials (67.1% vs 51.3%, respectively) as was the disease control rate (89.9% vs 78.8%, respectively), though it varied by race/ethnicity, ECOG, and prior treatment history. Discontinuation (0.0%) and dose reductions (3.4%) due to adverse events were uncommon in alectinib. Patients using alectinib post-crizotinib in clinical practice are older, more racially/ethnically and histologically diverse than patients in published trials. Real-world response rates were high and similar to those reported in clinical studies, though there is some variation by patient characteristics. Alectinib was well tolerated in clinical practice as reflected by the rates of discontinuation, dose reductions, and dose interruptions.

Meniscus Induced Cartilaginous Damage and Non-linear Gross Anatomical Progression of Early-stage Osteoarthritis in a Canine Model

PubMed Central

Kahn, David; Mittelstaedt, Daniel; Matyas, John; Qu, Xiangui; Lee, Ji Hyun; Badar, Farid; Les, Clifford; Zhuang, Zhiguo; Xia, Yang

2016-01-01

Background: The predictable outcome of the anterior cruciate ligament transection (ACLT) canine model, and the similarity to naturally occurring osteoarthritis (OA) in humans, provide a translatable method for studying OA. Still, evidence of direct meniscus-induced cartilaginous damage has not been identified, and gross-anatomical blinded scoring of early-stage OA has not been performed. Objective: A gross anatomical observation and statistical analysis of OA progression to determine meniscus induced cartilaginous damage, to measure the macroscopic progression of OA, and to address matters involving arthroscopic and surgical procedures of the knee. Method: Unblinded assessment and blinded scoring of meniscal, tibial, femoral, and patellar damage were performed for control and at four time points following unilateral ACLT: 3-week (N=4), 8-week (N=4), 12-week (N=5), and 25-week (N=4). Mixed-model statistics illustrates damage (score) progression; Wilcoxon rank-sum tests compared time-point scores; and Wilcoxon signed-rank tests compared ACLT and contralateral scores, and meniscus and tibia scores. Result: Damage was manifest first on the posterior aspect of the medial meniscus and subsequently on the tibia and femur, implying meniscal damage can precede, coincide with, and aggravate cartilage damage. Damage extent varied chronologically and was dependent upon the joint component. Meniscal damage was evident at 3 weeks and progressed through 25-weeks. Meniscal loose bodies corresponded to tibial cartilage damage location and extent through 12 weeks, followed by cartilage repair activity after complete meniscal degeneration. Conclusion: This study provides additional information for understanding OA progression, identifying OA biomarkers, and arthroscopic and meniscectomy procedures. PMID:28144379

Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma.

PubMed

McGuire, Mary F; Sriram Iyengar, M; Mercer, David W

2012-04-01

Although trauma is the leading cause of death for those below 45years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. In the node/molecular analysis of the first 24h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships--activation, expression, inhibition, and transcription--and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction

Data driven linear algebraic methods for analysis of molecular pathways: application to disease progression in shock/trauma

PubMed Central

McGuire, Mary F.; Iyengar, M. Sriram; Mercer, David W.

2012-01-01

Motivation Although trauma is the leading cause of death for those below 45 years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. Results In the node/molecular analysis of the first 24 hours from trauma, PSA uncovered 7 molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which 3 molecules had not been previously associated with any shock / trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships – activation, expression, inhibition, and transcription – and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on

Microminiature linear split Stirling cryogenic cooler for portable infrared imagers

NASA Astrophysics Data System (ADS)

Veprik, A.; Vilenchik, H.; Riabzev, S.; Pundak, N.

2007-04-01

Novel tactics employed in carrying out military and antiterrorist operations call for the development of a new generation of warfare, among which sophisticated portable infrared (IR) imagers for surveillance, reconnaissance, targeting and navigation play an important role. The superior performance of such imagers relies on novel optronic technologies and maintaining the infrared focal plane arrays at cryogenic temperatures using closed cycle refrigerators. Traditionally, rotary driven Stirling cryogenic engines are used for this purpose. As compared to their military off-theshelf linear rivals, they are lighter, more compact and normally consume less electrical power. Latest technological advances in industrial development of high-temperature (100K) infrared detectors initialized R&D activity towards developing microminiature cryogenic coolers, both of rotary and linear types. On this occasion, split linearly driven cryogenic coolers appear to be more suitable for the above applications. Their known advantages include flexibility in the system design, inherently longer life time, low vibration export and superior aural stealth. Moreover, recent progress in designing highly efficient "moving magnet" resonant linear drives and driving electronics enable further essential reduction of the cooler size, weight and power consumption. The authors report on the development and project status of a novel Ricor model K527 microminiature split Stirling linear cryogenic cooler designed especially for the portable infrared imagers.

Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia.

PubMed

Rogalski, E; Cobia, D; Harrison, T M; Wieneke, C; Weintraub, S; Mesulam, M-M

2011-05-24

To examine the longitudinal course of primary progressive aphasia (PPA) over a 2-year period and to offer quantitative ranges of expected change that could be used to guide the design and evaluation of therapeutic intervention trials. Regional changes of cortical thickness and whole-brain cortical volume loss as well as neuropsychological language performance were assessed at baseline and 2 years later in 13 rigorously characterized patients who fulfilled research criteria for logopenic, agrammatic, and semantic PPA subtypes (6 PPA-L, 3 PPA-G, and 4 PPA-S). There was substantial progression of clinical deficits and cortical atrophy over 2 years. Neuropsychological language performance patterns lost the sharp distinctions that differentiated one PPA variant from another. Nonetheless, the subtype-specific differential impairment of word comprehension vs grammatical processing was largely maintained. Peak atrophy sites spread beyond the initial distinctive locations that characterized each of the 3 subtypes and displayed a more convergent distribution encompassing all 3 major components of the language network: the inferior frontal gyrus, the temporoparietal junction, and lateral temporal cortex. Despite the progression, overall peak atrophy remained lateralized to the left hemisphere. The results suggest that the unique features, which sharply differentiate the PPA variants at the early to middle stages, may lose their distinctiveness as the degeneration becomes more severe. Given the substantial atrophy over 2 years, PPA clinical trials may require fewer patients and shorter study durations than Alzheimer disease trials to detect significant therapeutic effects.

Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia

PubMed Central

Cobia, D.; Harrison, T.M.; Wieneke, C.; Weintraub, S.; Mesulam, M.-M.

2011-01-01

Objectives: To examine the longitudinal course of primary progressive aphasia (PPA) over a 2-year period and to offer quantitative ranges of expected change that could be used to guide the design and evaluation of therapeutic intervention trials. Methods: Regional changes of cortical thickness and whole-brain cortical volume loss as well as neuropsychological language performance were assessed at baseline and 2 years later in 13 rigorously characterized patients who fulfilled research criteria for logopenic, agrammatic, and semantic PPA subtypes (6 PPA-L, 3 PPA-G, and 4 PPA-S). Results: There was substantial progression of clinical deficits and cortical atrophy over 2 years. Neuropsychological language performance patterns lost the sharp distinctions that differentiated one PPA variant from another. Nonetheless, the subtype-specific differential impairment of word comprehension vs grammatical processing was largely maintained. Peak atrophy sites spread beyond the initial distinctive locations that characterized each of the 3 subtypes and displayed a more convergent distribution encompassing all 3 major components of the language network: the inferior frontal gyrus, the temporoparietal junction, and lateral temporal cortex. Despite the progression, overall peak atrophy remained lateralized to the left hemisphere. Conclusions: The results suggest that the unique features, which sharply differentiate the PPA variants at the early to middle stages, may lose their distinctiveness as the degeneration becomes more severe. Given the substantial atrophy over 2 years, PPA clinical trials may require fewer patients and shorter study durations than Alzheimer disease trials to detect significant therapeutic effects. PMID:21606451

A Three-Dimensional Linearized Unsteady Euler Analysis for Turbomachinery Blade Rows

NASA Technical Reports Server (NTRS)

Montgomery, Matthew D.; Verdon, Joseph M.

1997-01-01

A three-dimensional, linearized, Euler analysis is being developed to provide an efficient unsteady aerodynamic analysis that can be used to predict the aeroelastic and aeroacoustic responses of axial-flow turbo-machinery blading.The field equations and boundary conditions needed to describe nonlinear and linearized inviscid unsteady flows through a blade row operating within a cylindrical annular duct are presented. A numerical model for linearized inviscid unsteady flows, which couples a near-field, implicit, wave-split, finite volume analysis to a far-field eigenanalysis, is also described. The linearized aerodynamic and numerical models have been implemented into a three-dimensional linearized unsteady flow code, called LINFLUX. This code has been applied to selected, benchmark, unsteady, subsonic flows to establish its accuracy and to demonstrate its current capabilities. The unsteady flows considered, have been chosen to allow convenient comparisons between the LINFLUX results and those of well-known, two-dimensional, unsteady flow codes. Detailed numerical results for a helical fan and a three-dimensional version of the 10th Standard Cascade indicate that important progress has been made towards the development of a reliable and useful, three-dimensional, prediction capability that can be used in aeroelastic and aeroacoustic design studies.

Cross-section Trichometry: A Clinical Tool for Assessing the Progression and Treatment Response of Alopecia

PubMed Central

Wikramanayake, Tongyu Cao; Mauro, Lucia M; Tabas, Irene A; Chen, Anne L; Llanes, Isabel C; Jimenez, Joaquin J

2012-01-01

Background: To properly assess the progression and treatment response of alopecia, one must measure the changes in hair mass, which is influenced by both the density and diameter of hair. Unfortunately, a convenient device for hair mass evaluation had not been available to dermatologists until the recent introduction of the cross-section trichometer, which directly measures the cross-sectional area of an isolated bundle of hair. Objective: We sought to evaluate the accuracy and sensitivity of the HairCheck® device, a commercial product derived from the original cross-section trichometer. Materials and Methods: Bundles of surgical silk and human hair were used to evaluate the ability of the HairCheck® device to detect and measure small changes in the number and diameter of strands, and bundle weight. Results: Strong correlations were observed between the bundle's cross-sectional area, displayed as the numeric Hair Mass Index (HMI), the number of strands, the silk/hair diameter, and the bundle dry weight. Conclusion: HMI strongly correlated with the number and diameter of silk/hair, and the weight of the bundle, suggesting that it can serve as a valid indicator of hair mass. We have given the name cross-section trichometry (CST) to the methodology of obtaining the HMI using the HairCheck® system. CST is a simple modality for the quantification of hair mass, and may be used as a convenient and useful tool to clinically assess changes in hair mass caused by thinning, shedding, breakage, or growth in males and females with progressive alopecia or those receiving alopecia treatment. PMID:23766610

[Progress in methodological characteristics of clinical practice guideline for osteoarthritis].

PubMed

Xing, D; Wang, B; Lin, J H

2017-06-01

At present, several clinical practice guidelines for the treatment of osteoarthritis have been developed by institutes or societies. The ultimate purpose of developing clinical practice guidelines is to formulate the process in the treatment of osteoarthritis effectively. However, the methodologies used in developing clinical practice guidelines may place an influence on the transformation and application of that in treating osteoarthritis. The present study summarized the methodological features of individual clinical practice guideline and presented the tools for quality evaluation of clinical practice guideline. The limitations of current osteoarthritis guidelines of China are also indicated. The review article might help relevant institutions improve the quality in developing guide and clinical transformation.

Stochastic modeling of mode interactions via linear parabolized stability equations

NASA Astrophysics Data System (ADS)

Ran, Wei; Zare, Armin; Hack, M. J. Philipp; Jovanovic, Mihailo

2017-11-01

Low-complexity approximations of the Navier-Stokes equations have been widely used in the analysis of wall-bounded shear flows. In particular, the parabolized stability equations (PSE) and Floquet theory have been employed to capture the evolution of primary and secondary instabilities in spatially-evolving flows. We augment linear PSE with Floquet analysis to formally treat modal interactions and the evolution of secondary instabilities in the transitional boundary layer via a linear progression. To this end, we leverage Floquet theory by incorporating the primary instability into the base flow and accounting for different harmonics in the flow state. A stochastic forcing is introduced into the resulting linear dynamics to model the effect of nonlinear interactions on the evolution of modes. We examine the H-type transition scenario to demonstrate how our approach can be used to model nonlinear effects and capture the growth of the fundamental and subharmonic modes observed in direct numerical simulations and experiments.

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias

PubMed Central

Gan, Shi-Rui; Wang, Jie; Figueroa, Karla P.; Pulst, Stefan M.; Tomishon, Darya; Lee, Danielle; Perlman, Susan; Wilmot, George; Gomez, Christopher M.; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G.; Ying, Sarah H.; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D.; Xia, Guangbin; Subramony, S. H.; Ashizawa, Tetsuo; Kuo, Sheng-Han

2017-01-01

Background Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. Methods We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Results Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = –0.91, p < 0.001; SCA6, β = –1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = –1.53, p = 0.037) and ATXN3 (β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = –0.40, p = 0.032). Discussion Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor. PMID:29057148

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias.

PubMed

Gan, Shi-Rui; Wang, Jie; Figueroa, Karla P; Pulst, Stefan M; Tomishon, Darya; Lee, Danielle; Perlman, Susan; Wilmot, George; Gomez, Christopher M; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G; Ying, Sarah H; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D; Xia, Guangbin; Subramony, S H; Ashizawa, Tetsuo; Kuo, Sheng-Han

2017-01-01

Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = -0.91, p < 0.001; SCA6, β = -1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = -1.53, p = 0.037) and ATXN3 (β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = -0.40, p = 0.032). Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.

Clinical and Immunological Markers of Dengue Progression in a Study Cohort from a Hyperendemic Area in Malaysia

PubMed Central

Rathakrishnan, Anusyah; Klekamp, Benjamin; Wang, Seok Mui; Komarasamy, Thamil Vaani; Natkunam, Santha Kumari; Sathar, Jameela; Azizan, Azliyati; Sanchez-Anguiano, Aurora; Manikam, Rishya; Sekaran, Shamala Devi

2014-01-01

Background With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification. Methodology and Findings This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness. Conclusion The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings. PMID:24647042

Defining active progressive multiple sclerosis.

PubMed

Sellebjerg, Finn; Börnsen, Lars; Ammitzbøll, Cecilie; Nielsen, Jørgen Erik; Vinther-Jensen, Tua; Hjermind, Lena Elisabeth; von Essen, Marina; Ratzer, Rikke Lenhard; Soelberg Sørensen, Per; Romme Christensen, Jeppe

2017-11-01

It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

Nonoperative Management, Rehabilitation, and Functional and Clinical Progression of Osteitis Pubis/Pubic Bone Stress in Professional Soccer Players: A Case Series.

PubMed

McAleer, Stephen S; Lippie, Ed; Norman, Darcy; Riepenhof, Helge

2017-09-01

Study Design Case series. Background Pubic bone stress (PBS) is a common acute or chronic response of the pelvis in sports where sprinting, kicking, twisting, and cutting are the dominant movements. There are few nonoperative rehabilitation strategies for the condition reported in the literature, and the outcome of conservative treatment has not been documented. Case Description Five professional and academy soccer players complaining of pubic symphysis pain, confirmed as PBS on magnetic resonance imaging and objective assessment, were treated with a nonoperative rehabilitation program that featured functional and clinical objective markers as progression criteria. Interventions in the acute phase included pharmacological and physical therapeutic modalities to reduce pain initially. Rehabilitation management focused on improving range of motion at the hips and thorax, adductor strengthening, trunk and lumbopelvic stability, gym-based strength training, and field-based rehabilitation and conditioning. Clinical follow-up was performed at least 8 months following return to play. Outcomes All players demonstrated reduced or resolved pain, increased adductor squeeze strength, and return to pain-free training and match play. Return-to-training time averaged 40.6 days (range, 30-60 days) and return to play averaged 49.4 days (range, 38-72 days) within the 5 players. At final follow-up (mean, 29.6 months; range, 16-33 months), there had been no recurrences. Discussion This report of 5 cases suggests that a nonoperative protocol, using clinical and functional progression criteria, may be successful in rehabilitating athletes with PBS for return to sport within 11 weeks. Level of Evidence Therapy, level 4. J Orthop Sports Phys Ther 2017;47(9):683-690. Epub 3 Aug 2017. doi:10.2519/jospt.2017.7314.

Nanoparticle Motion in Entangled Melts of Linear and Nonconcatenated Ring Polymers

PubMed Central

2017-01-01

The motion of nanoparticles (NPs) in entangled melts of linear polymers and nonconcatenated ring polymers are compared by large-scale molecular dynamics simulations. The comparison provides a paradigm for the effects of polymer architecture on the dynamical coupling between NPs and polymers in nanocomposites. Strongly suppressed motion of NPs with diameter d larger than the entanglement spacing a is observed in a melt of linear polymers before the onset of Fickian NP diffusion. This strong suppression of NP motion occurs progressively as d exceeds a and is related to the hopping diffusion of NPs in the entanglement network. In contrast to the NP motion in linear polymers, the motion of NPs with d > a in ring polymers is not as strongly suppressed prior to Fickian diffusion. The diffusion coefficient D decreases with increasing d much slower in entangled rings than in entangled linear chains. NP motion in entangled nonconcatenated ring polymers is understood through a scaling analysis of the coupling between NP motion and the self-similar entangled dynamics of ring polymers. PMID:28392603

Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms.

PubMed

Zhang, Yong; Kong, Weijia; Jiang, Jiandong

2017-06-01

Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression, and spread of cancer, in which proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and transcription factors, such as nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-κB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products (green tea catechins, andrographolide, curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation-related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future.

Progress in Geriatrics: A Clinical Care Update.

ERIC Educational Resources Information Center

Blanchette, Patricia Lanoie; And Others

1997-01-01

This issue includes 18 theme articles that examine clinical care, conditions, and practice as they relate to older adults. It contains articles on the following: men's and women's health, depression, dementia, hypertension, incontinence, bone pain, infections, preventive medicine, geriatric medicine, health care delivery, managed care, long-term…

Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries.

PubMed

Wall, Kristin M; Rida, Wasima; Haddad, Lisa B; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H; Latka, Mary H; Anzala, Omu; Sanders, Eduard J; Bekker, Linda-Gail; Edward, Vinodh A; Price, Matt A

2017-03-01

Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/μl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/μl or a single CD4 ≤350 cells/μl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted.

Role of Chronic Inflammation in Myopia Progression: Clinical Evidence and Experimental Validation.

PubMed

Lin, Hui-Ju; Wei, Chang-Ching; Chang, Ching-Yao; Chen, Ter-Hsin; Hsu, Yu-An; Hsieh, Yi-Ching; Chen, Hsuan-Ju; Wan, Lei

2016-08-01

Prevention and treatment of myopia is an important public problem worldwide. We found a higher incidence of myopia among patients with inflammatory diseases such as type 1 diabetes mellitus (7.9%), uveitis (3.7%), or systemic lupus erythematosus (3.5%) compared to those without inflammatory diseases (p<0.001) using data from children (<18years old) in the National Health Insurance Research database. We then examined the inhibition of myopia by atropine in Syrian hamsters with monocular form deprivation (MFD), an experimental myopia model. We found atropine downregulated inflammation in MFD eyes. The expression levels of c-Fos, nuclear factor κB (NFκB), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were upregulated in myopic eyes and downregulated upon treatment with atropine. The relationship between the inflammatory response and myopia was investigated by treating MFD hamsters with the immunosuppressive agent cyclosporine A (CSA) or the inflammatory stimulators lipopolysaccharide (LPS) or peptidoglycan (PGN). Myopia progression was slowed by CSA application but was enhanced by LPS and PGN administration. The levels of c-Fos, NF-κB, IL-6, and TNF-α were upregulated in LPS- and PGN-treated eyes and downregulated by CSA treatment. These findings provide clinical and experimental evidence that inflammation plays a crucial role in the development of myopia. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

An improved artifact removal in exposure fusion with local linear constraints

NASA Astrophysics Data System (ADS)

Zhang, Hai; Yu, Mali

2018-04-01

In exposure fusion, it is challenging to remove artifacts because of camera motion and moving objects in the scene. An improved artifact removal method is proposed in this paper, which performs local linear adjustment in artifact removal progress. After determining a reference image, we first perform high-dynamic-range (HDR) deghosting to generate an intermediate image stack from the input image stack. Then, a linear Intensity Mapping Function (IMF) in each window is extracted based on the intensities of intermediate image and reference image, the intensity mean and variance of reference image. Finally, with the extracted local linear constraints, we reconstruct a target image stack, which can be directly used for fusing a single HDR-like image. Some experiments have been implemented and experimental results demonstrate that the proposed method is robust and effective in removing artifacts especially in the saturated regions of the reference image.

[Congenital linear nevus sebaceus].

PubMed

Linnemann, Anders; Bygum, Anette; Fenger-Grøn, Jesper

2011-09-05

An unusual case of nevus sebaceous is described. Nevus sebaceous is a congenital epidermal hamartoma of the skin and the predilection site is the head or neck. In this case the nevus followed the lines of Blaschko along the back of the left lower extremity. The linear lesion seemed papulovesicular which caused suspicion of incontinentia pigmenti or infection, and the boy received antimicrobial treatment until a biopsy revealed the correct diagnosis. We wish to emphasize this clinical picture to spare the patient and relatives from unnecessary tests, treatment and concern.

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

PubMed

Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

2015-01-01

Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

Enterprise digital assistants: the progression of wireless clinical computing.

PubMed

Bergeron, Bryan P

2002-01-01

By virtue of increasingly pervasive wireless connectivity, the proliferation of wireless handheld devices in clinical care is rapidly transforming the concept of the personal digital assistant (PDA) to the enterprise digital assistant (EDA). Wireless handheld devices are becoming extensions of the central hospital information system, in which it's understood that the health care enterprise, not the clinician carrying the information-dispensing device, owns the data. The practical implication for clinicians is that, despite the potential long-term benefits of seamless, just-in-time clinical data access, this paradigm shift portends decreased efficiency in the short term, as clinicians duplicate clinical data collection on private devices. Assuming eventual clinician acceptance, EDAs can form the basis of a national real-time clinical data acquisition system that ensures uniform prescribing, decision support, and diagnosis, and the means for tracking unusual disease presentation patterns that could be indicative of bioterrorism or natural disease outbreaks.

[THE FACTORS OF THE PROGRESSION OF METABOLIC DISORDERS IN THE PANCREAS IN PATIENTS WITH ASSOCIATED CLINICAL VARIANTS OF THE CHRONIC PANCREATITIS AND TYPE 2 DIABETES MELLITUS].

PubMed

Zhuravlyova, L V; Shekhovtsova, Y O

2015-01-01

The purpose of the present study was to determine the causal factors of the progression of metabolic disorders in pancreatic tissue and their relationships in patients with assotiated clinical variants of chronic pancreatitis (CP) and type 2 diabetes mellitus (T2DM). The study involved of 76 patients with CP and T2DM. The causes of progression of metabolic disorders in the pancreas in patients with associated clinical variants of CP and T2DM has been analyzed. The most significant of them were insulin resistance and abdominal obesity, which promotes early formation of the metabolic syndrome and the activation of fibrogenesis and steatosis in the pancreas and is caused by dyslipidemia, impaired glucose metabolism and the development of systemic inflammation and imbalance of adipocytokines. The relationships between adipocytokines, body weight and individual components of the metabolic syndrome in patients with CP and T2DM suggests the involvement of these hormones of adipose tissue in the formation of the metabolic syndrome and its components.

Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

PubMed Central

Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortés, Claudia P; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro

2016-01-01

Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings. PMID:27065108

Clinical ethics revisited

PubMed Central

Singer, Peter A; Pellegrino, Edmund D; Siegler, Mark

2001-01-01

A decade ago, we reviewed the field of clinical ethics; assessed its progress in research, education, and ethics committees and consultation; and made predictions about the future of the field. In this article, we revisit clinical ethics to examine our earlier observations, highlight key developments, and discuss remaining challenges for clinical ethics, including the need to develop a global perspective on clinical ethics problems. PMID:11346456

Tri-linear interpolation-based cerebral white matter fiber imaging

PubMed Central

Jiang, Shan; Zhang, Pengfei; Han, Tong; Liu, Weihua; Liu, Meixia

2013-01-01

Diffusion tensor imaging is a unique method to visualize white matter fibers three-dimensionally, non-invasively and in vivo, and therefore it is an important tool for observing and researching neural regeneration. Different diffusion tensor imaging-based fiber tracking methods have been already investigated, but making the computing faster, fiber tracking longer and smoother and the details shown clearer are needed to be improved for clinical applications. This study proposed a new fiber tracking strategy based on tri-linear interpolation. We selected a patient with acute infarction of the right basal ganglia and designed experiments based on either the tri-linear interpolation algorithm or tensorline algorithm. Fiber tracking in the same regions of interest (genu of the corpus callosum) was performed separately. The validity of the tri-linear interpolation algorithm was verified by quantitative analysis, and its feasibility in clinical diagnosis was confirmed by the contrast between tracking results and the disease condition of the patient as well as the actual brain anatomy. Statistical results showed that the maximum length and average length of the white matter fibers tracked by the tri-linear interpolation algorithm were significantly longer. The tracking images of the fibers indicated that this method can obtain smoother tracked fibers, more obvious orientation and clearer details. Tracking fiber abnormalities are in good agreement with the actual condition of patients, and tracking displayed fibers that passed though the corpus callosum, which was consistent with the anatomical structures of the brain. Therefore, the tri-linear interpolation algorithm can achieve a clear, anatomically correct and reliable tracking result. PMID:25206524

Linear lichen planus in children - Case report*

PubMed Central

Horowitz, Marcia Raquel; Vidal, Marcela de Lima; Resende, Manuela Oliveira; Teixeira, Márcia Almeida Galvão; Cavalcanti, Silvana Maria de Morais; de Alencar, Eliane Ruth Barbosa

2013-01-01

Lichen planus is an uncommon disease in children, and only 2 to 3% of affected patients are under twenty years of age. This dermatosis may appear in several clinical forms, which vary according to the morphology and distribution of lesions. In less than 0.2% of all lichen planus cases, the lesions are distributed along the lines of Blaschko, and is a variant called linear lichen planus. This is a case report of a patient aged two years and eight months, who presented keratotic violaceous papules, affecting the abdomen, buttocks and right thigh, distributed along the lines of Blaschko. Histopathological examination confirmed a diagnosis of linear lichen planus. PMID:24346902

Integer Linear Programming in Computational Biology

NASA Astrophysics Data System (ADS)

Althaus, Ernst; Klau, Gunnar W.; Kohlbacher, Oliver; Lenhof, Hans-Peter; Reinert, Knut

Computational molecular biology (bioinformatics) is a young research field that is rich in NP-hard optimization problems. The problem instances encountered are often huge and comprise thousands of variables. Since their introduction into the field of bioinformatics in 1997, integer linear programming (ILP) techniques have been successfully applied to many optimization problems. These approaches have added much momentum to development and progress in related areas. In particular, ILP-based approaches have become a standard optimization technique in bioinformatics. In this review, we present applications of ILP-based techniques developed by members and former members of Kurt Mehlhorn’s group. These techniques were introduced to bioinformatics in a series of papers and popularized by demonstration of their effectiveness and potential.

Progressive Decrease of Peripapillary Angioflow Vessel Density During Structural and Visual Field Progression in Early Primary Open-angle Glaucoma.

PubMed

Holló, Gábor

2017-07-01

To present a case of early primary open-angle glaucoma in which retinal nerve fiber layer thickness (RNFLT), ganglion cell complex (GCC), and visual field progression were accompanied with significant progression of peripapillary angioflow vessel density (PAFD) measured with optical coherence tomographic angiography. A 68-year-old female patient who was under topical intraocular pressure (IOP) lowering medication for 20 years for ocular hypertension of the right and preperimetric primary open-angle glaucoma of the left eye (with reproducible inferotemporal and superotemporal neuroretinal rim and RNFL loss) was prospectively imaged with the AngioVue OCT for RNFLT, GCC thickness, and PAFD, and investigated with the Octopus Normal G2 visual field test on the same days at 6-month intervals for 18 months, while the IOP of the left eye escaped from control. IOP of the left eye fluctuated between 14 and 30 mm Hg in the study period. RNFLT, GCC thickness, and peripapillary PAFD all decreased significantly (linear regression analysis, P=0.030, 0.040, and 0.020, respectively), and a significant 2.1 dB/y progression was seen for a superior visual field cluster. The RNFLT, peripapillary PAFD, and visual field of the right eye remained normal and unchanged. In our case IOP elevation, glaucomatous visual field conversion, and structural progression were accompanied with significant progressive decrease of peripapillary PAFD. The simultaneous thinning of RNFLT and GCC and decrease of peripapillary PAFD suggest that PAFD may potentially be an additional indicator of early progression in primary open-angle glaucoma.

Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers.

PubMed

Handels, Ron L H; Vos, Stephanie J B; Kramberger, Milica G; Jelic, Vesna; Blennow, Kaj; van Buchem, Mark; van der Flier, Wiesje; Freund-Levi, Yvonne; Hampel, Harald; Olde Rikkert, Marcel; Oleksik, Ania; Pirtosek, Zvezdan; Scheltens, Philip; Soininen, Hilkka; Teunissen, Charlotte; Tsolaki, Magda; Wallin, Asa K; Winblad, Bengt; Verhey, Frans R J; Visser, Pieter Jelle

2017-08-01

We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia. The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers. Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up. An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

The Relationship Between Caffeine Intake and Immunological and Virological Markers of HIV Disease Progression in Miami Adult Studies on HIV Cohort.

PubMed

Ramamoorthy, Venkataraghavan; Campa, Adriana; Rubens, Muni; Martinez, Sabrina S; Fleetwood, Christina; Stewart, Tiffanie; Liuzzi, Juan P; George, Florence; Khan, Hafiz; Li, Yinghui; Baum, Marianna K

2017-05-01

Although there are many studies on adverse health effects of substance use and HIV disease progression, similar studies about caffeine consumption are few. In this study, we investigated the effects of caffeine on immunological and virological markers of HIV disease progression. A convenience sample of 130 clinically stable people living with HIV/AIDS on antiretroviral therapy (65 consuming ≤250 mg/day and 65 consuming >250 mg/day of caffeine) were recruited from the Miami Adult Studies on HIV (MASH) cohort. This study included a baseline and 3-month follow-up visit. Demographics, body composition measures, substance use, Modified Caffeine Consumption Questionnaire (MCCQ), and CD4 count and HIV viral load were obtained for all participants. Multivariable linear regression and Linear Mixed Models (LMMs) were used to understand the effect of caffeine consumption on CD4 count and HIV viral load. The mean age of the cohort was 47.9 ± 6.4 years, 60.8% were men and 75.4% were African Americans. All participants were on ART during both the visits. Mean caffeine intake at baseline was 337.6 ± 305.0 mg/day and did not change significantly at the 3-month follow-up visit. Multivariable linear regressions after adjustment for covariates showed significant association between caffeine consumption and higher CD4 count (β = 1.532, p = 0.049) and lower HIV viral load (β = -1.067, p = 0.048). LMM after adjustment for covariates showed that the relationship between caffeine and CD4 count (β = 1.720, p = 0.042) and HIV viral load (β = -1.389, p = 0.033) continued over time in a dose-response manner. Higher caffeine consumption was associated with higher CD4 cell counts and lower HIV viral loads indicating beneficial effects on HIV disease progression. Further studies examining biochemical effects of caffeine on CD4 cell counts and viral replication need to be done in the future.

[Rapidly progressive glomerulonephritis: a diagnostic and therapeutic emergency].

PubMed

Halfon, Matthieu; Teta, Daniel; Rotman, Samuel; Pruijm, Menno; Humbert, Antoine

2014-02-26

Rapidly progressive glomerulonephritis (RPG) is a rare clinical syndrome characterized by kidney damage that can lead to irreversible kidney failure. RPG can be caused by primary glomerular disease or can be part of a systemic autoimmune disorder. All RPG have a similar pathophysiology (proliferation of cells in Bowman's capsule and formation of crescents) and clinical evolution (rapidly progressive kidney failure with proteinuria and an active urine sediment). Immunosuppressive therapy and sometimes plasma exchanges are required. Overall- and kidney survival are closely linked to the blood creatinine level at presentation, the percentage of damaged glomeruli, and to the underlying cause. RPG is therefore a diagnostic and therapeutic emergency that needs quick referral to a nephrologist.

Haemodynamic and anatomic progression of aortic stenosis.

PubMed

Nguyen, Virginia; Cimadevilla, Claire; Estellat, Candice; Codogno, Isabelle; Huart, Virginie; Benessiano, Joelle; Duval, Xavier; Pibarot, Philippe; Clavel, Marie Annick; Enriquez-Sarano, Maurice; Vahanian, Alec; Messika-Zeitoun, David

2015-06-01

Aortic valve stenosis (AS) is a progressive disease, but the impact of baseline AS haemodynamic or anatomic severity on AS progression remains unclear. In 149 patients (104 mild AS, 36 moderate AS and 9 severe AS) enrolled in 2 ongoing prospective cohorts (COFRASA/GENERAC), we evaluated AS haemodynamic severity at baseline and yearly, thereafter, using echocardiography (mean pressure gradient (MPG)) and AS anatomic severity using CT (degree of aortic valve calcification (AVC)). After a mean follow-up of 2.9±1.0 years, mean MGP increased from 22±11 to 30±16 mm Hg (+3±3 mm Hg/year), and mean AVC from 1108±891 to 1640±1251 AU (arbitrary units) (+188±176 AU/year). Progression of AS was strongly related to baseline haemodynamic severity (+2±3 mm Hg/year in mild AS, +4±3 mm Hg/year in moderate AS and +5±5 mm Hg/year in severe AS (p=0.01)), and baseline haemodynamic severity was an independent predictor of haemodynamic progression (p=0.0003). Annualised haemodynamic and anatomic progression rates were significantly correlated (r=0.55, p<0.0001), but AVC progression rate was also significantly associated with baseline haemodynamic severity (+141±133 AU/year in mild AS, +279±189 AU/year in moderate AS and +361±293 AU/year in severe AS, p<0.0001), and both baseline MPG and baseline AVC were independent determinants of AVC progression (p<0.0001). AS progressed faster with increasing haemodynamic or anatomic severity. Our results suggest that a medical strategy aimed at preventing AVC progression may be useful in all subsets of patients with AS including those with severe AS and support the recommended closer follow-up of patients with AS as AS severity increases. COFRASA (clinicalTrial.gov number NCT 00338676) and GENERAC (clinicalTrial.gov number NCT00647088). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Non-linear models for the detection of impaired cerebral blood flow autoregulation.

PubMed

Chacón, Max; Jara, José Luis; Miranda, Rodrigo; Katsogridakis, Emmanuel; Panerai, Ronney B

2018-01-01

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model's derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired.

Non-linear models for the detection of impaired cerebral blood flow autoregulation

PubMed Central

Miranda, Rodrigo; Katsogridakis, Emmanuel

2018-01-01

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model’s derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired. PMID:29381724

LINEAR - DERIVATION AND DEFINITION OF A LINEAR AIRCRAFT MODEL

NASA Technical Reports Server (NTRS)

Duke, E. L.

1994-01-01

The Derivation and Definition of a Linear Model program, LINEAR, provides the user with a powerful and flexible tool for the linearization of aircraft aerodynamic models. LINEAR was developed to provide a standard, documented, and verified tool to derive linear models for aircraft stability analysis and control law design. Linear system models define the aircraft system in the neighborhood of an analysis point and are determined by the linearization of the nonlinear equations defining vehicle dynamics and sensors. LINEAR numerically determines a linear system model using nonlinear equations of motion and a user supplied linear or nonlinear aerodynamic model. The nonlinear equations of motion used are six-degree-of-freedom equations with stationary atmosphere and flat, nonrotating earth assumptions. LINEAR is capable of extracting both linearized engine effects, such as net thrust, torque, and gyroscopic effects and including these effects in the linear system model. The point at which this linear model is defined is determined either by completely specifying the state and control variables, or by specifying an analysis point on a trajectory and directing the program to determine the control variables and the remaining state variables. The system model determined by LINEAR consists of matrices for both the state and observation equations. The program has been designed to provide easy selection of state, control, and observation variables to be used in a particular model. Thus, the order of the system model is completely under user control. Further, the program provides the flexibility of allowing alternate formulations of both the state and observation equations. Data describing the aircraft and the test case is input to the program through a terminal or formatted data files. All data can be modified interactively from case to case. The aerodynamic model can be defined in two ways: a set of nondimensional stability and control derivatives for the flight point of

A prototype piecewise-linear dynamic attenuator

NASA Astrophysics Data System (ADS)

Hsieh, Scott S.; Peng, Mark V.; May, Christopher A.; Shunhavanich, Picha; Fleischmann, Dominik; Pelc, Norbert J.

2016-07-01

The piecewise-linear dynamic attenuator has been proposed as a mechanism in CT scanning for personalizing the x-ray illumination on a patient- and application-specific basis. Previous simulations have shown benefits in image quality, scatter, and dose objectives. We report on the first prototype implementation. This prototype is reduced in scale and speed and is integrated into a tabletop CT system with a smaller field of view (25 cm) and longer scan time (42 s) compared to a clinical system. Stainless steel wedges were machined and affixed to linear actuators, which were in turn held secure by a frame built using rapid prototyping technologies. The actuators were computer-controlled, with characteristic noise of about 100 microns. Simulations suggest that in a clinical setting, the impact of actuator noise could lead to artifacts of only 1 HU. Ring artifacts were minimized by careful design of the wedges. A water beam hardening correction was applied and the scan was collimated to reduce scatter. We scanned a 16 cm water cylinder phantom as well as an anthropomorphic pediatric phantom. The artifacts present in reconstructed images are comparable to artifacts normally seen with this tabletop system. Compared to a flat-field reference scan, increased detectability at reduced dose is shown and streaking is reduced. Artifacts are modest in our images and further refinement is possible. Issues of mechanical speed and stability in the challenging clinical CT environment will be addressed in a future design.

Comparing the sensitivity of linear and volumetric MRI measurements to detect changes in the size of vestibular schwannomas in patients with neurofibromatosis type 2 on bevacizumab treatment.

PubMed

Morris, Katrina A; Parry, Allyson; Pretorius, Pieter M

2016-09-01

To compare the sensitivity of linear and volumetric measurements on MRI in detecting schwannoma progression in patients with neurofibromatosis type 2 on bevacizumab treatment as well as the extent to which this depends on the size of the tumour. We compared retrospectively, changes in linear tumour dimensions at a range of thresholds to volumetric tumour measurements performed using Brainlab iPlan(®) software (Feldkirchen, Germany) and classified for tumour progression according to the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Assessment of 61 schwannomas in 46 patients with a median follow-up of 20 months (range 3-43 months) was performed. There was a mean of 7 time points per tumour (range 2-12 time points). Using the volumetric REiNS criteria as the gold standard, a sensitivity of 86% was achieved for linear measurement using a 2-mm threshold to define progression. We propose that a change in linear measurement by 2 mm (particularly in tumours with starting diameters 20-30 mm, the majority of this cohort) could be used as a filter to identify cases of possible progression requiring volumetric analysis. This pragmatic approach can be used if stabilization of a previously growing schwannoma is sufficient for a patient to continue treatment in such a circumstance. We demonstrate the real-world limitations of linear vs volumetric measurement in tumour response assessment and identify limited circumstances where linear measurements can be used to determine which patients require the more resource-intensive volumetric measurements.

Polyaniline-graphene based α-amylase biosensor with a linear dynamic range in excess of 6 orders of magnitude.

PubMed

Teixeira, Sofia Rodrigues; Lloyd, Catherine; Yao, Seydou; Andrea Salvatore Gazze; Whitaker, Iain S; Francis, Lewis; Conlan, R Steven; Azzopardi, Ernest

2016-11-15

α-amylase is an established marker for diagnosis of pancreatic and salivary disease, and recent research has seen a substantial expansion of its use in therapeutic and diagnostic applications for infection, cancer and wound healing. The lack of bedside monitoring devices for α-amylase detection has hitherto restricted the clinical progress of such applications. We have developed a highly sensitive α-amylase immunosensor platform, produced via in situ electropolymerization of aniline onto a screen-printed graphene support (SPE). Covalently binding an α-amylase specific antibody to a polyaniline (PANI) layer and controlling device assembly using electrochemical impedance spectroscopy (EIS), we have achieved a highly linear response against α-amylase concentration. Each stage of the assembly was characterized using a suite of high-resolution topographical, chemical and mechanical techniques. Quantitative, highly sensitive detection was demonstrated using an artificially spiked human blood plasma samples. The device has a remarkably wide limit of quantification (0.025-1000IU/L) compared to α-amylase assays in current clinical use. With potential for simple scale up to volume manufacturing though standard semiconductor production techniques and subsequently clinical application, this biosensor will enable clinical benefit through early disease detection, and better informed administration of correct therapeutic dose of drugs used to treat α-amylase related diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

PubMed

Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

2014-10-01

We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

PubMed

Stone, A M; Bushnell, W; Denne, J; Sargent, D J; Amit, O; Chen, C; Bailey-Iacona, R; Helterbrand, J; Williams, G

2011-08-01

Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Impact of Human Papilloma Viruses, Matrix Metallo-Proteinases and HIV Protease Inhibitors on the Onset and Progression of Uterine Cervix Epithelial Tumors: A Review of Preclinical and Clinical Studies

PubMed Central

Barillari, Giovanni; Monini, Paolo

2018-01-01

Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent and aggressive in women infected by both HPV and the Human Immunodeficiency Virus (HIV), as compared to the general female population. In these individuals, however, therapeutic regimens employing HIV protease inhibitors (HIV-PI) have reduced CIN incidence and/or clinical progression, shedding light on the mechanism(s) of its development. This article reviews published work concerning: (i) the role of HPV proteins (including HPV-E5, E6 and E7) and of matrix-metalloproteinases (MMPs) in CIN evolution into invasive CC; and (ii) the effect of HIV-PI on events leading to CIN progression such as basement membrane and extracellular matrix invasion by HPV-positive CIN cells and the formation of new blood vessels. Results from the reviewed literature indicate that CIN clinical progression can be monitored by evaluating the expression of MMPs and HPV proteins and they suggest the use of HIV-PI or their derivatives for the block of CIN evolution into CC in both HIV-infected and uninfected women. PMID:29747434

On the linear programming bound for linear Lee codes.

PubMed

Astola, Helena; Tabus, Ioan

2016-01-01

Based on an invariance-type property of the Lee-compositions of a linear Lee code, additional equality constraints can be introduced to the linear programming problem of linear Lee codes. In this paper, we formulate this property in terms of an action of the multiplicative group of the field [Formula: see text] on the set of Lee-compositions. We show some useful properties of certain sums of Lee-numbers, which are the eigenvalues of the Lee association scheme, appearing in the linear programming problem of linear Lee codes. Using the additional equality constraints, we formulate the linear programming problem of linear Lee codes in a very compact form, leading to a fast execution, which allows to efficiently compute the bounds for large parameter values of the linear codes.

Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease.

PubMed

Cholerton, Brenna; Johnson, Catherine O; Fish, Brian; Quinn, Joseph F; Chung, Kathryn A; Peterson-Hiller, Amie L; Rosenthal, Liana S; Dawson, Ted M; Albert, Marilyn S; Hu, Shu-Ching; Mata, Ignacio F; Leverenz, James B; Poston, Kathleen L; Montine, Thomas J; Zabetian, Cyrus P; Edwards, Karen L

2018-05-01

Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Performance and reliability enhancement of linear coolers

NASA Astrophysics Data System (ADS)

Mai, M.; Rühlich, I.; Schreiter, A.; Zehner, S.

2010-04-01

Highest efficiency states a crucial requirement for modern tactical IR cryocooling systems. For enhancement of overall efficiency, AIM cryocooler designs where reassessed considering all relevant loss mechanisms and associated components. Performed investigation was based on state-of-the-art simulation software featuring magnet circuitry analysis as well as computational fluid dynamics (CFD) to realistically replicate thermodynamic interactions. As a result, an improved design for AIM linear coolers could be derived. This paper gives an overview on performance enhancement activities and major results. An additional key-requirement for cryocoolers is reliability. In recent time, AIM has introduced linear coolers with full Flexure Bearing suspension on both ends of the driving mechanism incorporating Moving Magnet piston drive. In conjunction with a Pulse-Tube coldfinger these coolers are capable of meeting MTTF's (Mean Time To Failure) in excess of 50,000 hours offering superior reliability for space applications. Ongoing development also focuses on reliability enhancement, deriving space technology into tactical solutions combining both, excelling specific performance with space like reliability. Concerned publication will summarize the progress of this reliability program and give further prospect.

Progress in the detection of neoplastic progress and cancer by Raman spectroscopy

NASA Astrophysics Data System (ADS)

Bakker Schut, Tom C.; Stone, Nicholas; Kendall, Catherine A.; Barr, Hugh; Bruining, Hajo A.; Puppels, Gerwin J.

2000-05-01

Early detection of cancer is important because of the improved survival rates when the cancer is treated early. We study the application of NIR Raman spectroscopy for detection of dysplasia because this technique is sensitive to the small changes in molecular invasive in vivo detection using fiber-optic probes. The result of an in vitro study to detect neoplastic progress of esophageal Barrett's esophageal tissue will be presented. Using multivariate statistics, we developed three different linear discriminant analysis classification models to predict tissue type on the basis of the measured spectrum. Spectra of normal, metaplastic and dysplasia tissue could be discriminated with an accuracy of up to 88 percent. Therefore Raman spectroscopy seems to be a very suitable technique to detect dysplasia in Barrett's esophageal tissue.

Progress in evidence-based medicine: a quarter century on.

PubMed

Djulbegovic, Benjamin; Guyatt, Gordon H

2017-07-22

In response to limitations in the understanding and use of published evidence, evidence-based medicine (EBM) began as a movement in the early 1990s. EBM's initial focus was on educating clinicians in the understanding and use of published literature to optimise clinical care, including the science of systematic reviews. EBM progressed to recognise limitations of evidence alone, and has increasingly stressed the need to combine critical appraisal of the evidence with patient's values and preferences through shared decision making. In another progress, EBM incorporated and further developed the science of producing trustworthy clinical practice guidelines pioneered by investigators in the 1980s. EBM's enduring contributions to clinical medicine include placing the practice of medicine on a solid scientific basis, the development of more sophisticated hierarchies of evidence, the recognition of the crucial role of patient values and preferences in clinical decision making, and the development of the methodology for generating trustworthy recommendations. Copyright © 2017 Elsevier Ltd. All rights reserved.

The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies.

PubMed

van Leeuwen, C M; Oei, A L; Crezee, J; Bel, A; Franken, N A P; Stalpers, L J A; Kok, H P

2018-05-16

Prediction of radiobiological response is a major challenge in radiotherapy. Of several radiobiological models, the linear-quadratic (LQ) model has been best validated by experimental and clinical data. Clinically, the LQ model is mainly used to estimate equivalent radiotherapy schedules (e.g. calculate the equivalent dose in 2 Gy fractions, EQD 2 ), but increasingly also to predict tumour control probability (TCP) and normal tissue complication probability (NTCP) using logistic models. The selection of accurate LQ parameters α, β and α/β is pivotal for a reliable estimate of radiation response. The aim of this review is to provide an overview of published values for the LQ parameters of human tumours as a guideline for radiation oncologists and radiation researchers to select appropriate radiobiological parameter values for LQ modelling in clinical radiotherapy. We performed a systematic literature search and found sixty-four clinical studies reporting α, β and α/β for tumours. Tumour site, histology, stage, number of patients, type of LQ model, radiation type, TCP model, clinical endpoint and radiobiological parameter estimates were extracted. Next, we stratified by tumour site and by tumour histology. Study heterogeneity was expressed by the I 2 statistic, i.e. the percentage of variance in reported values not explained by chance. A large heterogeneity in LQ parameters was found within and between studies (I 2  > 75%). For the same tumour site, differences in histology partially explain differences in the LQ parameters: epithelial tumours have higher α/β values than adenocarcinomas. For tumour sites with different histologies, such as in oesophageal cancer, the α/β estimates correlate well with histology. However, many other factors contribute to the study heterogeneity of LQ parameters, e.g. tumour stage, type of LQ model, TCP model and clinical endpoint (i.e. survival, tumour control and biochemical control). The value of LQ parameters for

Prognosis Research Strategy (PROGRESS) 2: prognostic factor research.

PubMed

Riley, Richard D; Hayden, Jill A; Steyerberg, Ewout W; Moons, Karel G M; Abrams, Keith; Kyzas, Panayiotis A; Malats, Núria; Briggs, Andrew; Schroter, Sara; Altman, Douglas G; Hemingway, Harry

2013-01-01

Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Unsteady Solution of Non-Linear Differential Equations Using Walsh Function Series

NASA Technical Reports Server (NTRS)

Gnoffo, Peter A.

2015-01-01

Walsh functions form an orthonormal basis set consisting of square waves. The discontinuous nature of square waves make the system well suited for representing functions with discontinuities. The product of any two Walsh functions is another Walsh function - a feature that can radically change an algorithm for solving non-linear partial differential equations (PDEs). The solution algorithm of non-linear differential equations using Walsh function series is unique in that integrals and derivatives may be computed using simple matrix multiplication of series representations of functions. Solutions to PDEs are derived as functions of wave component amplitude. Three sample problems are presented to illustrate the Walsh function series approach to solving unsteady PDEs. These include an advection equation, a Burgers equation, and a Riemann problem. The sample problems demonstrate the use of the Walsh function solution algorithms, exploiting Fast Walsh Transforms in multi-dimensions (O(Nlog(N))). Details of a Fast Walsh Reciprocal, defined here for the first time, enable inversion of aWalsh Symmetric Matrix in O(Nlog(N)) operations. Walsh functions have been derived using a fractal recursion algorithm and these fractal patterns are observed in the progression of pairs of wave number amplitudes in the solutions. These patterns are most easily observed in a remapping defined as a fractal fingerprint (FFP). A prolongation of existing solutions to the next highest order exploits these patterns. The algorithms presented here are considered a work in progress that provide new alternatives and new insights into the solution of non-linear PDEs.

PNPLA3 rs738409 polymorphism is associated with liver fibrosis progression in patients with chronic hepatitis C: A repeated measures study.

PubMed

Jiménez-Sousa, María Ángeles; Gómez-Moreno, Ana Zaida; Pineda-Tenor, Daniel; Sánchez-Ruano, Juan José; Fernández-Rodríguez, Amanda; Artaza-Varasa, Tomas; Gómez-Sanz, Alicia; Martín-Vicente, María; Vázquez-Morón, Sonia; Resino, Salvador

2018-06-01

Host genetic background has been associated with liver fibrosis progression. To analyze the association between the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. In this retrospective cohort study, 187 patients with chronic HCV infection were included, who had at least two liver stiffness measurements (LSM) by transient elastography during the follow-up. Results were expressed in kilopascals (kPa). The analysis of genetic association was carried out according to additive model by using Generalized Linear Models. No patients had advanced fibrosis/cirrhosis at baseline. During a median follow-up time of 47.9 months, 15 patients developed advanced fibrosis and 17 cirrhosis. In multivariate analysis adjusted by the main clinical and epidemiological covariates, the rs738409 G allele was related to higher increase of LSM values during the follow-up (adjusted arithmetic mean ratio (aAMR) = 1.16 (95%CI = 1.04; 1.29); p = .006) and higher odds of having progression to advanced fibrosis [aOR = 2.03 (95%CI = 1.01; 4.06); p = .045], and progression to cirrhosis [aOR = 3.03 (95%CI = 1.26; 7.30); p = .014]. PNPLA3 rs738409 polymorphism appears to be related to the increased progression of liver fibrosis in HCV infected patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Can Linear Superiorization Be Useful for Linear Optimization Problems?

PubMed Central

Censor, Yair

2017-01-01

Linear superiorization considers linear programming problems but instead of attempting to solve them with linear optimization methods it employs perturbation resilient feasibility-seeking algorithms and steers them toward reduced (not necessarily minimal) target function values. The two questions that we set out to explore experimentally are (i) Does linear superiorization provide a feasible point whose linear target function value is lower than that obtained by running the same feasibility-seeking algorithm without superiorization under identical conditions? and (ii) How does linear superiorization fare in comparison with the Simplex method for solving linear programming problems? Based on our computational experiments presented here, the answers to these two questions are: “yes” and “very well”, respectively. PMID:29335660

Real-world usage and clinical outcomes of alectinib among post-crizotinib progression anaplastic lymphoma kinase positive non-small-cell lung cancer patients in the USA

PubMed Central

DiBonaventura, Marco D; Wong, William; Shah-Manek, Bijal; Schulz, Mathias

2018-01-01

Background Alectinib is an approved treatment for anaplastic lymphoma kinase (ALK)-positive patients with advanced non-small-cell lung cancer. Despite positive supporting clinical data, there is a lack of real-world information on the usage and patient outcomes of those treated with alectinib post-crizotinib progression. Methods Participating oncologists (N=95) in the USA were recruited from an online physician panel to participate in a retrospective patient chart review. Physicians randomly selected eligible patients (ie, patients who progressed on crizotinib as their first ALK inhibitor and were treated with alectinib as their second ALK inhibitor), collected demographics and clinical history from their medical charts, and entered the data into an online data collection form. Results A total of N=207 patient charts were included (age: 60.1±10.4 years; 53.6% male). The patients in our sample were older (median age of 60 vs 53 years), were more likely to be current smokers (12% vs 1%), had better performance status (45% vs 33% had an Eastern Cooperative Oncology Group [ECOG] of 0), and were less likely to have an adenocarcinoma histology (83% vs 96%) relative to published clinical trials. The objective response rate was higher than in clinical trials (67.1% vs 51.3%, respectively) as was the disease control rate (89.9% vs 78.8%, respectively), though it varied by race/ethnicity, ECOG, and prior treatment history. Discontinuation (0.0%) and dose reductions (3.4%) due to adverse events were uncommon in alectinib. Conclusion Patients using alectinib post-crizotinib in clinical practice are older, more racially/ethnically and histologically diverse than patients in published trials. Real-world response rates were high and similar to those reported in clinical studies, though there is some variation by patient characteristics. Alectinib was well tolerated in clinical practice as reflected by the rates of discontinuation, dose reductions, and dose interruptions. PMID

Glaucoma progression detection by retinal nerve fiber layer measurement using scanning laser polarimetry: event and trend analysis.

PubMed

Moon, Byung Gil; Sung, Kyung Rim; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S

2012-06-01

To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression.

A linearly frequency-swept high-speed-rate multi-wavelength laser for optical coherence tomography

NASA Astrophysics Data System (ADS)

Wang, Qiyu; Wang, Zhaoying; Yuan, Quan; Ma, Rui; Du, Tao; Yang, Tianxin

2017-02-01

We proposed and demonstrated a linearly frequency-swept multi-wavelength laser source for optical coherence tomography (OCT) eliminating the need of wavenumber space resampling in the postprocessing progress. The source consists of a multi-wavelength fiber laser source (MFS) and an optical sweeping loop. In this novel laser source, an equally spaced multi-wavelength laser is swept simultaneously by a certain step each time in the frequency domain in the optical sweeping loop. The sweeping step is determined by radio frequency (RF) signal which can be precisely controlled. Thus the sweeping behavior strictly maintains a linear relationship between time and frequency. We experimentally achieved linear time-frequency sweeping at a sweeping rate of 400 kHz with our laser source.

HIV-1 DNA predicts disease progression and post-treatment virological control

PubMed Central

Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan

2014-01-01

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20 DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

Caffeine, creatine, GRIN2A and Parkinson's disease progression.

PubMed

Simon, David K; Wu, Cai; Tilley, Barbara C; Lohmann, Katja; Klein, Christine; Payami, Haydeh; Wills, Anne-Marie; Aminoff, Michael J; Bainbridge, Jacquelyn; Dewey, Richard; Hauser, Robert A; Schaake, Susen; Schneider, Jay S; Sharma, Saloni; Singer, Carlos; Tanner, Caroline M; Truong, Daniel; Wei, Peng; Wong, Pei Shieen; Yang, Tianzhong

2017-04-15

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Application of Nearly Linear Solvers to Electric Power System Computation

NASA Astrophysics Data System (ADS)

Grant, Lisa L.

To meet the future needs of the electric power system, improvements need to be made in the areas of power system algorithms, simulation, and modeling, specifically to achieve a time frame that is useful to industry. If power system time-domain simulations could run in real-time, then system operators would have situational awareness to implement online control and avoid cascading failures, significantly improving power system reliability. Several power system applications rely on the solution of a very large linear system. As the demands on power systems continue to grow, there is a greater computational complexity involved in solving these large linear systems within reasonable time. This project expands on the current work in fast linear solvers, developed for solving symmetric and diagonally dominant linear systems, in order to produce power system specific methods that can be solved in nearly-linear run times. The work explores a new theoretical method that is based on ideas in graph theory and combinatorics. The technique builds a chain of progressively smaller approximate systems with preconditioners based on the system's low stretch spanning tree. The method is compared to traditional linear solvers and shown to reduce the time and iterations required for an accurate solution, especially as the system size increases. A simulation validation is performed, comparing the solution capabilities of the chain method to LU factorization, which is the standard linear solver for power flow. The chain method was successfully demonstrated to produce accurate solutions for power flow simulation on a number of IEEE test cases, and a discussion on how to further improve the method's speed and accuracy is included.

Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.

PubMed

Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P

2016-10-18

To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.

Primary progressive aphasia: from syndrome to disease.

PubMed

Matías-Guiu, J A; García-Ramos, R

2013-01-01

Primary progressive aphasia (PPA) is a clinical syndrome characterised by a progressive decline in language and speech of neurodegenerative origin. Major breakthroughs made in recent years have lent us a better understanding of this syndrome, which may be the first manifestation of any of a number of neurodegenerative diseases. We reviewed the main aspects of PPA epidemiology, clinical manifestations, diagnosis, aetiology and treatment. Most cases manifest sporadically and the typical age of onset is between 50 and 70 years. Three clinically distinct variants have been described: nonfluent or agrammatic PPA, semantic PPA and logopenic PPA. Each of these variants tends to be associated with specific histopathological findings, but clinical diagnostic methods are imperfect predictors of underlying pathology. Anatomical and functional neuroimaging can provide useful biomarkers. Several treatments have been proposed, and while no clear benefits have been demonstrated, acetylcholinesterase inhibitors may be useful, especially in the logopenic variant. PPA is an emerging syndrome which may be more prevalent than we might expect. It was previously listed as part of the frontotemporal dementia spectrum, and it is also related to Alzheimer disease. Clinical diagnosis, complemented by a biomarker evaluation, may predict the underlying pathology, which in turn will improve treatment possibilities. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Role of Statistical Random-Effects Linear Models in Personalized Medicine

PubMed Central

Diaz, Francisco J; Yeh, Hung-Wen; de Leon, Jose

2012-01-01

Some empirical studies and recent developments in pharmacokinetic theory suggest that statistical random-effects linear models are valuable tools that allow describing simultaneously patient populations as a whole and patients as individuals. This remarkable characteristic indicates that these models may be useful in the development of personalized medicine, which aims at finding treatment regimes that are appropriate for particular patients, not just appropriate for the average patient. In fact, published developments show that random-effects linear models may provide a solid theoretical framework for drug dosage individualization in chronic diseases. In particular, individualized dosages computed with these models by means of an empirical Bayesian approach may produce better results than dosages computed with some methods routinely used in therapeutic drug monitoring. This is further supported by published empirical and theoretical findings that show that random effects linear models may provide accurate representations of phase III and IV steady-state pharmacokinetic data, and may be useful for dosage computations. These models have applications in the design of clinical algorithms for drug dosage individualization in chronic diseases; in the computation of dose correction factors; computation of the minimum number of blood samples from a patient that are necessary for calculating an optimal individualized drug dosage in therapeutic drug monitoring; measure of the clinical importance of clinical, demographic, environmental or genetic covariates; study of drug-drug interactions in clinical settings; the implementation of computational tools for web-site-based evidence farming; design of pharmacogenomic studies; and in the development of a pharmacological theory of dosage individualization. PMID:23467392

Role of Statistical Random-Effects Linear Models in Personalized Medicine.

PubMed

Diaz, Francisco J; Yeh, Hung-Wen; de Leon, Jose

2012-03-01

Some empirical studies and recent developments in pharmacokinetic theory suggest that statistical random-effects linear models are valuable tools that allow describing simultaneously patient populations as a whole and patients as individuals. This remarkable characteristic indicates that these models may be useful in the development of personalized medicine, which aims at finding treatment regimes that are appropriate for particular patients, not just appropriate for the average patient. In fact, published developments show that random-effects linear models may provide a solid theoretical framework for drug dosage individualization in chronic diseases. In particular, individualized dosages computed with these models by means of an empirical Bayesian approach may produce better results than dosages computed with some methods routinely used in therapeutic drug monitoring. This is further supported by published empirical and theoretical findings that show that random effects linear models may provide accurate representations of phase III and IV steady-state pharmacokinetic data, and may be useful for dosage computations. These models have applications in the design of clinical algorithms for drug dosage individualization in chronic diseases; in the computation of dose correction factors; computation of the minimum number of blood samples from a patient that are necessary for calculating an optimal individualized drug dosage in therapeutic drug monitoring; measure of the clinical importance of clinical, demographic, environmental or genetic covariates; study of drug-drug interactions in clinical settings; the implementation of computational tools for web-site-based evidence farming; design of pharmacogenomic studies; and in the development of a pharmacological theory of dosage individualization.

Clinical synovitis in a particular joint is associated with progression of erosions and joint space narrowing in that same joint, but not in patients initially treated with infliximab.

PubMed

Klarenbeek, N B; Güler-Yüksel, M; van der Heijde, D M F M; Hulsmans, H M J; Kerstens, P J S M; Molenaar, T H E; de Sonnaville, P B J; Huizinga, T W J; Dijkmans, B A C; Allaart, C F

2010-12-01

To assess the relationship between joint tenderness, swelling and joint damage progression in individual joints and to evaluate the influence of treatment on these relationships. First-year data of the Behandel Strategieën (BeSt) study were used, in which patients recently diagnosed as having rheumatoid arthritis (RA) were randomly assigned into four different treatment strategies. Baseline and 1-year x-rays of the hands and feet were assessed using the Sharp-van der Heijde score (SHS). With generalised estimating equations, 3-monthly assessments of tender and swollen joints of year 1 were related to erosion progression, joint space narrowing (JSN) progression and total SHS progression at the individual joint level (definition > 0.5 SHS units) in year 1, corrected for potential confounders and within-patient correlation for multiple joints per patient. During year 1, 59% of all 13 959 joints analysed were ever tender and 45% ever swollen, 2.1% showed erosion progression, 1.9% JSN progression and 3.6% SHS progression. Swelling and tenderness were both independently associated with erosion and JSN progression with comparable OR, although with higher OR in the hands than in the feet. Local swelling and tenderness were not associated with local damage progression in patients initially treated with infliximab. Clinical signs of synovitis are associated with erosion and JSN progression in individual joints after 1 year in RA. A disconnect between synovitis and joint damage progression was observed at joint level in patients who were treated with methotrexate and infliximab as initial treatment, confirming the disconnect between synovitis and the development of joint damage in tumour necrosis factor blockers seen at patient level.

Estimating mono- and bi-phasic regression parameters using a mixture piecewise linear Bayesian hierarchical model

PubMed Central

Zhao, Rui; Catalano, Paul; DeGruttola, Victor G.; Michor, Franziska

2017-01-01

The dynamics of tumor burden, secreted proteins or other biomarkers over time, is often used to evaluate the effectiveness of therapy and to predict outcomes for patients. Many methods have been proposed to investigate longitudinal trends to better characterize patients and to understand disease progression. However, most approaches assume a homogeneous patient population and a uniform response trajectory over time and across patients. Here, we present a mixture piecewise linear Bayesian hierarchical model, which takes into account both population heterogeneity and nonlinear relationships between biomarkers and time. Simulation results show that our method was able to classify subjects according to their patterns of treatment response with greater than 80% accuracy in the three scenarios tested. We then applied our model to a large randomized controlled phase III clinical trial of multiple myeloma patients. Analysis results suggest that the longitudinal tumor burden trajectories in multiple myeloma patients are heterogeneous and nonlinear, even among patients assigned to the same treatment cohort. In addition, between cohorts, there are distinct differences in terms of the regression parameters and the distributions among categories in the mixture. Those results imply that longitudinal data from clinical trials may harbor unobserved subgroups and nonlinear relationships; accounting for both may be important for analyzing longitudinal data. PMID:28723910

Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease.

PubMed

Hamelin, Lorraine; Lagarde, Julien; Dorothée, Guillaume; Potier, Marie Claude; Corlier, Fabian; Kuhnast, Bertrand; Caillé, Fabien; Dubois, Bruno; Fillon, Ludovic; Chupin, Marie; Bottlaender, Michel; Sarazin, Marie

2018-06-01

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4

Modelling the Progression of Competitive Performance of an Academy's Soccer Teams.

PubMed

Malcata, Rita M; Hopkins, Will G; Richardson, Scott

2012-01-01

Progression of a team's performance is a key issue in competitive sport, but there appears to have been no published research on team progression for periods longer than a season. In this study we report the game-score progression of three teams of a youth talent-development academy over five seasons using a novel analytic approach based on generalised mixed modelling. The teams consisted of players born in 1991, 1992 and 1993; they played totals of 115, 107 and 122 games in Asia and Europe between 2005 and 2010 against teams differing in age by up to 3 years. Game scores predicted by the mixed model were assumed to have an over-dispersed Poisson distribution. The fixed effects in the model estimated an annual linear pro-gression for Aspire and for the other teams (grouped as a single opponent) with adjustment for home-ground advantage and for a linear effect of age difference between competing teams. A random effect allowed for different mean scores for Aspire and opposition teams. All effects were estimated as factors via log-transformation and presented as percent differences in scores. Inferences were based on the span of 90% confidence intervals in relation to thresholds for small factor effects of x/÷1.10 (+10%/-9%). Most effects were clear only when data for the three teams were combined. Older teams showed a small 27% increase in goals scored per year of age difference (90% confidence interval 13 to 42%). Aspire experienced a small home-ground advantage of 16% (-5 to 41%), whereas opposition teams experienced 31% (7 to 60%) on their own ground. After adjustment for these effects, the Aspire teams scored on average 1.5 goals per match, with little change in the five years of their existence, whereas their opponents' scores fell from 1.4 in their first year to 1.0 in their last. The difference in progression was trivial over one year (7%, -4 to 20%), small over two years (15%, -8 to 44%), but unclear over >2 years. In conclusion, the generalized mixed model

Early Detection of Progressive Adolescent Idiopathic Scoliosis: A Severity Index.

PubMed

Skalli, Wafa; Vergari, Claudio; Ebermeyer, Eric; Courtois, Isabelle; Drevelle, Xavier; Kohler, Remi; Abelin-Genevois, Kariman; Dubousset, Jean

2017-06-01

Early detection of progressive adolescent idiopathic scoliosis (AIS) was assessed based on 3D quantification of the deformity. Based on 3D quantitative description of scoliosis curves, the aim is to assess a specific phenotype that could be an early detectable severity index for progressive AIS. Early detection of progressive scoliosis is important for adapted treatment to limit progression. However, progression risk assessment is mainly based on the follow up, waiting for signs of rapid progression that generally occur during the growth peak. Sixty-five mild scoliosis (16 boys, 49 girls, Cobb Angle between 10 and 20°) with a Risser between 0 and 2 were followed from their first examination until a decision was made by the clinician, either considering the spine as stable at the end of growth (26 patients) or planning to brace because of progression (39 patients). Calibrated biplanar x-rays were performed and 3D reconstructions of the spine allowed calculating six local parameters related to main curve deformity. For progressive curve 3D phenotype assessment, data were compared with those previously assessed for 30 severe scoliosis (Cobb Angle > 35°), 17 scoliosis before brace (Cobb Angle > 29°) and 53 spines of nonscoliosis subjects. A predictive discriminant analysis was performed to assess similarity of mild scoliosis curves either to those of scoliosis or nonscoliosis spines, yielding a severity index (S-index). S-index value at first examination was compared with clinical outcome. At the first exam, 53 out of 65 predictions (82%) were in agreement with actual clinical outcome. Approximately, 89% of the curves that were predicted as progressive proved accurate. Although still requiring large scale validation, results are promising for early detection of progressive curves. 2.

Advances in high power linearly polarized fiber laser and its application

NASA Astrophysics Data System (ADS)

Zhou, Pu; Huang, Long; Ma, Pengfei; Xu, Jiangming; Su, Rongtao; Wang, Xiaolin

2017-10-01

Fiber lasers are now attracting more and more research interest due to their advantages in efficiency, beam quality and flexible operation. Up to now, most of the high power fiber lasers have random distributed polarization state. Linearlypolarized (LP) fiber lasers, which could find wide application potential in coherent detection, coherent/spectral beam combining, nonlinear frequency conversion, have been a research focus in recent years. In this paper, we will present a general review on the achievements of various kinds of high power linear-polarized fiber laser and its application. The recent progress in our group, including power scaling by using power amplifier with different mechanism, high power linearly polarized fiber laser with diversified properties, and various applications of high power linear-polarized fiber laser, are summarized. We have achieved 100 Watt level random distributed feedback fiber laser, kilowatt level continuous-wave (CW) all-fiber polarization-maintained fiber amplifier, 600 watt level average power picosecond polarization-maintained fiber amplifier and 300 watt level average power femtosecond polarization-maintained fiber amplifier. In addition, high power linearly polarized fiber lasers have been successfully applied in 5 kilowatt level coherent beam combining, structured light field and ultrasonic generation.

Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries

PubMed Central

Rida, Wasima; Haddad, Lisa B.; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H.; Latka, Mary H.; Anzala, Omu; Sanders, Eduard J.; Bekker, Linda-Gail; Edward, Vinodh A.; Price, Matt A.

2017-01-01

Background: Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. Methods: From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/μl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/μl or a single CD4 ≤350 cells/μl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. Results: Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. Conclusions: In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted. PMID:27893488

Maximizing the Prospects for Progress Against Cancer

Cancer.gov

The 2018 American Society of Clinical Oncology annual meeting featured numerous, potentially practice changing research findings, according to NCI Director Dr. Norman Sharpless. In this Cancer Currents post, Dr. Sharpless discusses the rapid pace of progress in cancer research.

Motor Speech Disorders Associated with Primary Progressive Aphasia

PubMed Central

Duffy, Joseph R.; Strand, Edythe A.; Josephs, Keith A.

2014-01-01

Background Primary progressive aphasia (PPA) and conditions that overlap with it can be accompanied by motor speech disorders. Recognition and understanding of motor speech disorders can contribute to a fuller clinical understanding of PPA and its management as well as its localization and underlying pathology. Aims To review the types of motor speech disorders that may occur with PPA, its primary variants, and its overlap syndromes (progressive supranuclear palsy syndrome, corticobasal syndrome, motor neuron disease), as well as with primary progressive apraxia of speech. Main Contribution The review should assist clinicians' and researchers' understanding of the relationship between motor speech disorders and PPA and its major variants. It also highlights the importance of recognizing neurodegenerative apraxia of speech as a condition that can occur with little or no evidence of aphasia. Conclusion Motor speech disorders can occur with PPA. Their recognition can contribute to clinical diagnosis and management of PPA and to understanding and predicting the localization and pathology associated with PPA variants and conditions that can overlap with them. PMID:25309017

Vemurafenib beyond progression in a patient with metastatic melanoma: a case report.

PubMed

Grimaldi, Antonio M; Simeone, Ester; Palla, Marco; Festino, Lucia; Caracò, Corrado; Mozzillo, Nicola; Petrillo, Antonella; Muto, Paolo; Ascierto, Paolo A

2015-04-01

The prognosis of metastatic melanoma has changed markedly in recent years because of the advent of newer targeted therapies such as BRAF inhibitors. However, the response to BRAF inhibitor therapy is frequently nondurable in patients with advanced melanoma. Novel approaches are thus needed to overcome resistance to these agents and to improve the management of advanced melanoma patients after disease progression. Here, we present the case of a 44-year-old man diagnosed with advanced melanoma in July 2010, harboring a BRAF mutation. Melanoma progressed during first-line chemotherapy with dacarbazine, but showed significant benefit after the initiation of vemurafenib on August 2011. Six months later, the patient experienced disease progression in left-obturator lymphadenopathy; still, anti-BRAF treatment was continued together with stereotactic radiotherapy, and was interrupted only shortly for intestinal occlusion secondary to melanoma metastasis of the bowel. When his conditions were stable, after 1 month of vemurafenib treatment discontinuation, anti-BRAF therapy was reinitiated, with a positive outcome. Vemurafenib treatment was definitively discontinued for disease progression in the brain, peritoneum, lymph node, intestine, and skin in March 2013, after about 20 months from initiation, and the patient died a few weeks later. The clinical case presented here shows that treatment beyond progression with vemurafenib can yield a survival benefit in melanoma patients whose disease progresses in a few sites, which can be treated with locoregional therapies. This clinical strategy needs further validation in prospective clinical trials.

Subacute sclerosing panencephalitis presenting as rapidly progressive young-onset dementia.

PubMed

Chakor, Rahul Tryambak; Santosh, Nandanavana Subbareddy

2013-07-01

Onset of dementia before 65 years of age is termed as young-onset dementia (YOD). Very little literature exists regarding the clinical features and diagnoses of dementia in younger individuals. We present a case series of four patients of age 10 to 23 years with severe dementia within 18 months of clinical onset (rapidly progressive dementia). Three patients had generalised periodic complexes typical of subacute sclerosing panencephalitis (SSPE) on electroencephalogram (EEG). All patients had elevated cerebrospinal fluid (CSF) IgG measles antibodies. Our case series highlights that SSPE is an important cause of rapidly progressive YOD in developing countries like India.

Clinical and diagnostic aspects of lymphedema.

PubMed

Keo, Hong H; Gretener, Silvia B; Staub, Daniel

2017-07-01

Lymphedema is a chronic, progressive, and common but often unrecognized condition. The diagnosis of lymphatic disease on clinical grounds alone remains a challenge. Without proper diagnosis, therapy is often delayed, allowing disease progression. There is a need for a practical diagnostic algorithm and its imaging technique to guide clinical decision-making. The aim of this topical review is to provide a practical approach for assessing patients with suspected lymphedema and to give a critical appraisal of currently available imaging modalities that are applied in clinical practice to diagnose and map lymphatic disease.

A Randomized Trial Using Progressive Addition Lenses to Evaluate Theories of Myopia Progression in Children with a High Lag of Accommodation

PubMed Central

Sinnott, Loraine T.; Mutti, Donald O.; Zadnik, Karla

2012-01-01

Purpose. To compare the effect of wearing, then ceasing to wear, progressive addition lenses (PALs) versus single vision lenses (SVLs) on myopia progression in children with high accommodative lag to evaluate accommodative lag and mechanical tension as theories of myopia progression. Methods. Eighty-five children (age range, 6–11 years) with spherical equivalent (SE) cycloplegic autorefraction between −0.75 D and −4.50 D were randomly assigned to wear SVLs or PALs for 1 year; all children wore SVLs a second year. Children had high accommodative lag and also had near esophoria if their myopia was greater than −2.25 D SE. The primary outcome after each year was the previous year's change in SE. Results. When the children were randomly assigned to SVLs or PALs, the adjusted 1-year changes in SE were −0.52 D (SVL group) and −0.35 D (PAL group; treatment effect = 0.18 D; P = 0.01). When all children wore SVLs the second year, there was no difference in myopia progression between SVL and former PAL wearers (0.06 D; P = 0.50). Accommodative lag was not associated with myopia progression. Conclusions. The statistically significant, but clinically small, PAL effect suggests that treatments aimed at reducing foveal defocus may not be as effective as previously thought in myopic children with high accommodative lag. Finding no evidence of treatment loss after discontinuing PAL wear supports hyperopic defocus-based theories such as accommodative lag; however, not finding an association between accommodative lag and myopia progression is inconsistent with the PAL effect being due to decreased foveal blur during near work. (Clinical Trials.gov number, NCT00335049.) PMID:22205604

Preemptive mechanical ventilation can block progressive acute lung injury.

PubMed

Sadowitz, Benjamin; Jain, Sumeet; Kollisch-Singule, Michaela; Satalin, Joshua; Andrews, Penny; Habashi, Nader; Gatto, Louis A; Nieman, Gary

2016-02-04

Mortality from acute respiratory distress syndrome (ARDS) remains unacceptable, approaching 45% in certain high-risk patient populations. Treating fulminant ARDS is currently relegated to supportive care measures only. Thus, the best treatment for ARDS may lie with preventing this syndrome from ever occurring. Clinical studies were examined to determine why ARDS has remained resistant to treatment over the past several decades. In addition, both basic science and clinical studies were examined to determine the impact that early, protective mechanical ventilation may have on preventing the development of ARDS in at-risk patients. Fulminant ARDS is highly resistant to both pharmacologic treatment and methods of mechanical ventilation. However, ARDS is a progressive disease with an early treatment window that can be exploited. In particular, protective mechanical ventilation initiated before the onset of lung injury can prevent the progression to ARDS. Airway pressure release ventilation (APRV) is a novel mechanical ventilation strategy for delivering a protective breath that has been shown to block progressive acute lung injury (ALI) and prevent ALI from progressing to ARDS. ARDS mortality currently remains as high as 45% in some studies. As ARDS is a progressive disease, the key to treatment lies with preventing the disease from ever occurring while it remains subclinical. Early protective mechanical ventilation with APRV appears to offer substantial benefit in this regard and may be the prophylactic treatment of choice for preventing ARDS.

[Current recommendations for deceleration of myopia progression].

PubMed

Lagrèze, W A; Joachimsen, L; Schaeffel, F

2017-01-01

Epidemiologic data demonstrate a rise in myopia prevalence. Therefore interventions to reduce the risk of myopia and its progression are needed and increasingly often asked for. Systematic literature search via PubMed in MEDLINE. Myopia progression can be reduced by the following means which are listed according to their efficacy: (1) Atropine eye drops low dosed to avoid clinically relevant side effects, (2) optical means aiming at the correction of peripheral hyperopic defocus, e. g., multifocal contact lenses, and (3) increased daylight exposure. Daylight exposure reduces the risk of incident myopia. Children should be advised to spend sufficient time outdoors, especially before and in primary school. Myopia progression can be effectively attenuated by low-dose topical atropine and multifocal contact lenses.

Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tranebjaerg, L.; Schwartz, C.; Huggins, K.

1994-07-15

In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localizedmore » to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.« less

Validating Variational Bayes Linear Regression Method With Multi-Central Datasets.

PubMed

Murata, Hiroshi; Zangwill, Linda M; Fujino, Yuri; Matsuura, Masato; Miki, Atsuya; Hirasawa, Kazunori; Tanito, Masaki; Mizoue, Shiro; Mori, Kazuhiko; Suzuki, Katsuyoshi; Yamashita, Takehiro; Kashiwagi, Kenji; Shoji, Nobuyuki; Asaoka, Ryo

2018-04-01

To validate the prediction accuracy of variational Bayes linear regression (VBLR) with two datasets external to the training dataset. The training dataset consisted of 7268 eyes of 4278 subjects from the University of Tokyo Hospital. The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) dataset consisted of 271 eyes of 177 patients, and the Diagnostic Innovations in Glaucoma Study (DIGS) dataset includes 248 eyes of 173 patients, which were used for validation. Prediction accuracy was compared between the VBLR and ordinary least squared linear regression (OLSLR). First, OLSLR and VBLR were carried out using total deviation (TD) values at each of the 52 test points from the second to fourth visual fields (VFs) (VF2-4) to 2nd to 10th VF (VF2-10) of each patient in JAMDIG and DIGS datasets, and the TD values of the 11th VF test were predicted every time. The predictive accuracy of each method was compared through the root mean squared error (RMSE) statistic. OLSLR RMSEs with the JAMDIG and DIGS datasets were between 31 and 4.3 dB, and between 19.5 and 3.9 dB. On the other hand, VBLR RMSEs with JAMDIG and DIGS datasets were between 5.0 and 3.7, and between 4.6 and 3.6 dB. There was statistically significant difference between VBLR and OLSLR for both datasets at every series (VF2-4 to VF2-10) (P < 0.01 for all tests). However, there was no statistically significant difference in VBLR RMSEs between JAMDIG and DIGS datasets at any series of VFs (VF2-2 to VF2-10) (P > 0.05). VBLR outperformed OLSLR to predict future VF progression, and the VBLR has a potential to be a helpful tool at clinical settings.

Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy.

PubMed

Koga, Tomohiro; Okada, Akitomo; Fukuda, Takaaki; Hidaka, Toshihiko; Ishii, Tomonori; Ueki, Yukitaka; Kodera, Takao; Nakashima, Munetoshi; Takahashi, Yuichi; Honda, Seiyo; Horai, Yoshiro; Watanabe, Ryu; Okuno, Hiroshi; Aramaki, Toshiyuki; Izumiyama, Tomomasa; Takai, Osamu; Miyashita, Taiichiro; Sato, Shuntaro; Kawashiri, Shin-Ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Origuchi, Tomoki; Nakamura, Hideki; Aoyagi, Kiyoshi; Eguchi, Katsumi; Kawakami, Atsushi

2016-04-01

To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01-1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17-2.59), RA typical erosion at baseline (95%CI 1.56-21.1), and the introduction of bDMARDs (95%CI 0.06-0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients' disease durations.

Periodontal profile classes predict periodontal disease progression and tooth loss.

PubMed

Morelli, Thiago; Moss, Kevin L; Preisser, John S; Beck, James D; Divaris, Kimon; Wu, Di; Offenbacher, Steven

2018-02-01

Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived

Do clinical and translational science graduate students understand linear regression? Development and early validation of the REGRESS quiz.

PubMed

Enders, Felicity

2013-12-01

Although regression is widely used for reading and publishing in the medical literature, no instruments were previously available to assess students' understanding. The goal of this study was to design and assess such an instrument for graduate students in Clinical and Translational Science and Public Health. A 27-item REsearch on Global Regression Expectations in StatisticS (REGRESS) quiz was developed through an iterative process. Consenting students taking a course on linear regression in a Clinical and Translational Science program completed the quiz pre- and postcourse. Student results were compared to practicing statisticians with a master's or doctoral degree in statistics or a closely related field. Fifty-two students responded precourse, 59 postcourse , and 22 practicing statisticians completed the quiz. The mean (SD) score was 9.3 (4.3) for students precourse and 19.0 (3.5) postcourse (P < 0.001). Postcourse students had similar results to practicing statisticians (mean (SD) of 20.1(3.5); P = 0.21). Students also showed significant improvement pre/postcourse in each of six domain areas (P < 0.001). The REGRESS quiz was internally reliable (Cronbach's alpha 0.89). The initial validation is quite promising with statistically significant and meaningful differences across time and study populations. Further work is needed to validate the quiz across multiple institutions. © 2013 Wiley Periodicals, Inc.

CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2: MacTel Project Report No. 6-The MacTel Research Group.

PubMed

Peto, Tunde; Heeren, Tjebo F C; Clemons, Traci E; Sallo, Ferenc B; Leung, Irene; Chew, Emily Y; Bird, Alan C

2018-01-01

To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (-1.40 ± 0.14 letters, P < 0.001). Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis

PubMed Central

Palekar, Rohun U.; Jallouk, Andrew P.; Goette, Matthew J.; Chen, Junjie; Myerson, Jacob W.; Allen, John S.; Akk, Antonina; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Pham, Christine T. N.; Wickline, Samuel A.; Pan, Hua

2015-01-01

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200–300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [19F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy.—Palekar, R. U., Jallouk, A. P., Goette, M. J., Chen, J., Myerson, J. W., Allen, J. S., Akk, A., Yang, L., Tu, Y., Miller, M. J., Pham, C. T. N., Wickline, S. A., Pan, H. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis. PMID:25857553

Glaucoma Progression Detection by Retinal Nerve Fiber Layer Measurement Using Scanning Laser Polarimetry: Event and Trend Analysis

PubMed Central

Moon, Byung Gil; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S.

2012-01-01

Purpose To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Methods Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Results Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. Conclusions RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression. PMID:22670073

Evidence for the Influence of the Iron Regulatory MHC Class I Molecule HFE on Tumor Progression in Experimental Models and Clinical Populations

PubMed Central

Weston, Cody; Connor, James

2014-01-01

Proteins involved in iron regulation are modifiers of cancer risk and progression. Of these, the HFE protein (high iron gene and its protein product) is of particular interest because of its interaction with both iron handling and immune function and the high rate of genetic polymorphisms resulting in a mutant protein. Clinical studies suggest that HFE polymorphisms increase the risk of certain cancers, but the inconsistent outcomes suggest a more nuanced effect, possibly interacting with other genetic or environmental factors. Some basic science research has been conducted to begin to understand the implications of variant HFE genotype on cancer, but the story is far from complete. In particular, putative mechanisms exist for HFE to affect tumor progression through its role in iron handling and its major histocompatibility complex class I structural features. In this review, the current understanding of the role of HFE in cancer is described and models for future directions are identified. PMID:25520556

Transcranial direct current stimulation in post stroke aphasia and primary progressive aphasia: Current knowledge and future clinical applications.

PubMed

Sebastian, Rajani; Tsapkini, Kyrana; Tippett, Donna C

2016-06-13

The application of transcranial direct current stimulation (tDCS) in chronic post stroke aphasia is documented in a substantial literature, and there is some new evidence that tDCS can augment favorable language outcomes in primary progressive aphasia. Anodal tDCS is most often applied to the left hemisphere language areas to increase cortical excitability (increase the threshold of activation) and cathodal tDCS is most often applied to the right hemisphere homotopic areas to inhibit over activation in contralesional right homologues of language areas. Outcomes usually are based on neuropsychological and language test performance, following a medical model which emphasizes impairment of function, rather than a model which emphasizes functional communication. In this paper, we review current literature of tDCS as it is being used as a research tool, and discuss future implementation of tDCS as an adjuvant treatment to behavioral speech-language pathology intervention. We review literature describing non-invasive brain stimulation, the mechanism of tDCS, and studies of tDCS in aphasia and neurodegenerative disorders. We discuss future clinical applications. tDCS is a promising adjunct to traditional speech-language pathology intervention to address speech-language deficits after stroke and in the neurodegenerative disease, primary progressive aphasia. Limited data are available regarding how performance on these types of specific tasks translates to functional communication outcomes.

Transcranial Direct Current Stimulation in Post Stroke Aphasia and Primary Progressive Aphasia: Current Knowledge and Future Clinical Applications

PubMed Central

Sebastian, Rajani; Tsapkini, Kyrana; Tippett, Donna C.

2016-01-01

BACKGROUND The application of transcranial direct current stimulation (tDCS) in chronic post stroke aphasia is documented in a substantial literature, and there is some new evidence that tDCS can augment favorable language outcomes in primary progressive aphasia. Anodal tDCS is most often applied to the left hemisphere language areas to increase cortical excitability (increase the threshold of activation) and cathodal tDCS is most often applied to the right hemisphere homotopic areas to inhibit over activation in contralesional right homologues of language areas. Outcomes usually are based on neuropsychological and language test performance, following a medical model which emphasizes impairment of function, rather than a model which emphasizes functional communication. OBJECTIVE In this paper, we review current literature of tDCS as it is being used as a research tool, and discuss future implementation of tDCS as an adjuvant treatment to behavioral speech-language pathology intervention. METHODS We review literature describing non-invasive brain stimulation, the mechanism of tDCS, and studies of tDCS in aphasia and neurodegenerative disorders. We discuss future clinical applications. RESULTS/CONCLUSIONS tDCS is a promising adjunct to traditional speech-language pathology intervention to address speech-language deficits after stroke and in the neurodegenerative disease, primary progressive aphasia. Limited data are available regarding how performance on these types of specific tasks translates to functional communication outcomes. PMID:27314871

Neuroimaging and clinical findings in a case of linear scleroderma en coup de sabre.

PubMed

Duman, Ikram E; Ekinci, Gazanfer

2018-06-01

Linear scleroderma "en coup de sabre" is a subset of localized scleroderma with band-like sclerotic lesions typically involving the frontoparietal regions of the scalp. En coup de sabre and Parry-Romberg syndrome are variants of linear morphea on the head and neck that can be associated with neurologic manifestations. On imaging, patients may have lesions in the cerebrum ipsilateral to the scalp abnormality. We present a case of an 8-year-old girl with a left frontoparietal "en coup de sabre" scalp lesion and describe the neuroimaging findings of frontoparietal white matter lesion discovered incidentally on routine magnetic resonance imaging. The patient had no neurologic symptoms given the lesion identified.

Image interpolation via regularized local linear regression.

PubMed

Liu, Xianming; Zhao, Debin; Xiong, Ruiqin; Ma, Siwei; Gao, Wen; Sun, Huifang

2011-12-01

The linear regression model is a very attractive tool to design effective image interpolation schemes. Some regression-based image interpolation algorithms have been proposed in the literature, in which the objective functions are optimized by ordinary least squares (OLS). However, it is shown that interpolation with OLS may have some undesirable properties from a robustness point of view: even small amounts of outliers can dramatically affect the estimates. To address these issues, in this paper we propose a novel image interpolation algorithm based on regularized local linear regression (RLLR). Starting with the linear regression model where we replace the OLS error norm with the moving least squares (MLS) error norm leads to a robust estimator of local image structure. To keep the solution stable and avoid overfitting, we incorporate the l(2)-norm as the estimator complexity penalty. Moreover, motivated by recent progress on manifold-based semi-supervised learning, we explicitly consider the intrinsic manifold structure by making use of both measured and unmeasured data points. Specifically, our framework incorporates the geometric structure of the marginal probability distribution induced by unmeasured samples as an additional local smoothness preserving constraint. The optimal model parameters can be obtained with a closed-form solution by solving a convex optimization problem. Experimental results on benchmark test images demonstrate that the proposed method achieves very competitive performance with the state-of-the-art interpolation algorithms, especially in image edge structure preservation. © 2011 IEEE

Departmental of Clinical Investigation: Annual Research Progress Report for Fiscal Year 1992. Volume 1

DTIC Science & Technology

1993-01-01

effect of cisapride on the symptoms of unexplained upper abdominal pain, nausea, vomiting, anorexia, early satiety, bloating/ distension in patients with...for 30 minutes following eccentric exercise will less the 3 indices of delayed-onset muscle soreness (DOMS): perceived muscular soreness, reduced...post-exercise and the Talag Pain Rating Scale will be used to assess muscular soreness. Progress: No progress report was furnished by the principal

Metabolic genes in cancer: their roles in tumor progression and clinical implications

PubMed Central

Furuta, Eiji; Okuda, Hiroshi; Kobayashi, Aya; Watabe, Kounosuke

2010-01-01

Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM1, RRM2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis. PMID:20122995

Progress in Understanding Autism: 2007-2010

ERIC Educational Resources Information Center

Rutter, Michael L.

2011-01-01

Scientific progress is discussed in relation to clinical issues; genetic issues; environmental issues; and the state of play on psychological treatments. It is concluded that substantial gains in knowledge have been achieved during the last 3 years, and there have been some unexpected findings, but major puzzles remain. We should be hopeful of…

CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.

PubMed

Rojas, Julio C; Bang, Jee; Lobach, Iryna V; Tsai, Richard M; Rabinovici, Gil D; Miller, Bruce L; Boxer, Adam L

2018-01-23

To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). We compared the ability of baseline CSF β-amyloid 1-42 , tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS ( p = 0.004, false discovery rate-corrected) and SEADL ( p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS ( p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL ( p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau ( p = 0.003) or NfL ( p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease. Copyright © 2017 American Academy of Neurology.

Medical students in their final six months of training: progress in self-perceived clinical competence, and relationship between experience and confidence in practical skills.

PubMed

Lai, N M; Sivalingam, N; Ramesh, J C

2007-11-01

We evaluated the progress in the self-perceived competence of medical students in a range of common clinical, practical and personal skills, in their final six months of training. The study was conducted on 65 final-year medical students undertaking their senior clerkship training at International Medical University, Malaysia. Questionnaire surveys were conducted at the beginning and the end of the six-month period, with 44 items covering clinical, practical, personal skills and readiness to work. Correlations were performed for experience and self-perceived competence, with the respective skills. 64 students returned the first survey and 63 returned the second survey. When the two survey results were compared, significant increases were found in self-perceived competence for the majority of the skills examined. The items with no significant improvement were divided into those which the students were already proficient in before senior clerkship, and those in which experience and confidence remained poor at the end of training. There were significant, but moderate, correlations between the experience and confidence of all common practical skills (correlation coefficients: 0.348-0.522, p-value is less than 0.001 for all items). At the end of training, students were, in general, more prepared to work as house officers (mean rating in the first survey: 3.05, second survey: 3.97, p-value is less than 0.001). Significant progresses in clinical experience and confidence can be observed in the final stages of medical training. The findings of inadequate improvements in some skills call for dedicated training sessions and strengthening of on-site supervision.

Natural progression of blood-induced joint damage in patients with haemophilia: clinical relevance and reproducibility of three-dimensional gait analysis.

PubMed

Lobet, S; Detrembleur, C; Francq, B; Hermans, C

2010-09-01

A major complication in haemophilia is the destruction of joint cartilage because of recurrent intraarticular and intramuscular bleeds. Therefore, joint assessment is critical to quantify the extent of joint damage, which has traditionally been evaluated using both radiological and clinical joint scores. Our study aimed to evaluate the natural progression of haemophilic arthopathy using three-dimensional gait analysis (3DGA) and to assess the reproducibility of this technique. We hypothesized that the musculoskeletal function was relatively stable in patients with haemophilia. Eighteen adults with established haemophilic arthropathies were evaluated twice by 3DGA (mean follow-up: 18 +/- 5 weeks). Unexpectedly, our findings revealed infraclinical deterioration of gait pattern, characterized by a 3.2% decrease in the recovery index, which is indicative of the subject's ability to save energy while walking. A tendency towards modification of segmental joint function was also observed. Gait analysis was sufficiently reproducible with regards to spatiotemporal parameters as well as kinetic, mechanical and energetic gait variables. The kinematic variables were reproducible in both the sagittal and frontal planes. In conclusion, 3DGA is a reproducible tool to assess abnormal gait patterns and monitor natural disease progression in haemophilic patients.

X-Linked Hereditary Nephropathy in Navasota Dogs: Clinical Pathology, Morphology, and Gene Expression During Disease Progression.

PubMed

Benali, S L; Lees, G E; Nabity, M B; Aricò, A; Drigo, M; Gallo, E; Giantin, M; Aresu, L

2016-07-01

X-linked hereditary nephropathy (XLHN) in Navasota dogs is a spontaneously occurring disease caused by a mutation resulting in defective production of type IV collagen and juvenile-onset renal failure. The study was aimed at examining the evolution of renal damage and the expression of selected molecules potentially involved in the pathogenesis of XLHN. Clinical data and renal samples were obtained in 10 XLHN male dogs and 5 controls at 4 (T0), 6 (T1), and 9 (T2) months of age. Glomerular and tubulointerstitial lesions were scored by light microscopy, and the expression of 21 molecules was investigated by quantitative real-time polymerase chain reaction with selected proteins evaluated by immunohistochemistry. No significant histologic lesions or clinicopathologic abnormalities were identified in controls at any time-point. XLHN dogs had progressive proteinuria starting at T0. At T1, XLHN dogs had a mesangioproliferative glomerulopathy with glomerular loss, tubular necrosis, and interstitial fibrosis. At T2, glomerular and tubulointerstitial lesions were more severe, particularly glomerular loss, interstitial fibrosis, and inflammation. At T0, transforming growth factor β, connective tissue growth factor, and platelet-derived growth factor α mRNA were overexpressed in XLHN dogs compared with controls. Clusterin and TIMP1 transcripts were upregulated in later stages of the disease. Transforming growth factor β, connective tissue growth factor, and platelet-derived growth factor α should be considered as key players in the initial events of XHLN. Clusterin and TIMP1 appear to be more associated with the progression rather than initiation of tubulointerstitial damage in chronic renal disease. © The Author(s) 2016.

Progress: Its Glories and Pitfalls.

PubMed

Callahan, Daniel

2018-03-01

Steven Pinker, a cognitive psychologist and linguist at Harvard and a savant of big ideas, is one of the latest to take on the idea of progress. He does it under the aegis of "enlightenment," which comes down to a kind of holy trinity of reason, science, and humanism. His new book, Enlightenment Now: The Case for Reason, Science, Humanism, and Progress, is ambitious and cantankerous and heady with hope. On the whole, Pinker makes a good case for the benefits of progress, but with an overdose of feel-good prose. His greatest failure comes in exaggerating the threats to science and in avoiding some problems altogether. He ignores its complexity, its shadows, its creation of new problems raised by its solutions to old ones. Pinker has a particular animus against bioethics, and he misses what has been, I would argue, at the heart of bioethics from its beginning fifty or so years ago. Bioethics was prompted by a new class of medical dilemmas that require a difficult balancing of harms and benefits. Most of them are still with us, and most of them are the result of the progress of postwar medical research and fast-changing clinical practices. © 2018 The Hastings Center.

Targeting the Progression of Parkinson’s Disease

PubMed Central

George, J.L; Mok, S; Moses, D; Wilkins, S; Bush, A.I; Cherny, R.A; Finkelstein, D.I

2009-01-01

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease. PMID:19721815

Computational approach for deriving cancer progression roadmaps from static sample data

PubMed Central

Yao, Jin; Yang, Le; Chen, Runpu; Nowak, Norma J.

2017-01-01

Abstract As with any biological process, cancer development is inherently dynamic. While major efforts continue to catalog the genomic events associated with human cancer, it remains difficult to interpret and extrapolate the accumulating data to provide insights into the dynamic aspects of the disease. Here, we present a computational strategy that enables the construction of a cancer progression model using static tumor sample data. The developed approach overcame many technical limitations of existing methods. Application of the approach to breast cancer data revealed a linear, branching model with two distinct trajectories for malignant progression. The validity of the constructed model was demonstrated in 27 independent breast cancer data sets, and through visualization of the data in the context of disease progression we were able to identify a number of potentially key molecular events in the advance of breast cancer to malignancy. PMID:28108658

Seeking a progressive relationship for learning: A theoretical scheme about the continuity of the student-educator relationship in clinical nursing education.

PubMed

Yaghoubinia, Fariba; Heydari, Abbas; Latifnejad Roudsari, Robab

2014-01-01

The student-educator relationship is an educational tool in nursing education and has long-lasting influence on the professional development of nursing students. Currently, this relationship in clinical settings is different from that in the past due to a paradigm shift in nursing education and its emphasis on the centrality of the relationship. The purpose of this grounded theory study was to explore the continuity of the student-educator relationship in the Iranian context of clinical nursing education. Ten bachelor nursing students and 10 clinical educators at Mashhad University of Medical Sciences, Iran, were selected through purposive and theoretical sampling. The data were collected through semi-structured interviews and participant observation. Interviews were transcribed verbatim, and data analysis was done through open, axial, and selective coding, using MAXQDA ver. 2007 qualitative data analysis software. The core category emerging from the data analysis was "seeking a progressive relationship for learning". Other major categories linked to and embraced within this core category were: "creating emotional connection", "trying to continue the relationship chain", and "adapting the behaviors". The findings indicated that in the Iranian sociocultural context, students and educators gain some action/interaction strategies for continuity of their relationship. It is obvious that the role of the nursing clinical educators and their relationship skills are critical in the relationship continuity of clinical settings. © 2013 The Authors. Japan Journal of Nursing Science © 2013 Japan Academy of Nursing Science.

When dementia progresses quickly: a practical approach to the diagnosis and management of rapidly progressive dementia.

PubMed

Day, Gregory S; Tang-Wai, David F

2014-01-01

Making a diagnosis of rapidly progressive dementia requires practical adaptation of the skills used to assess patients with chronic causes of cognitive impairment. An expedited assessment, commensurate with the accelerated pace of the disease, is required to identify the cause of symptoms amidst a myriad of possibilities. Features upon history, physical examination and cognitive assessment that support specific diagnoses are reviewed, and a stratified approach to testing is presented. The use of readily-accessible investigations is prioritized, acknowledging the implications and applications of novel diagnostic tests. The coordinated use of clinical and laboratory measures are promoted as a means of facilitating rapid evaluation, with the ultimate goal of identifying patients with potentially reversible causes of rapidly progressive dementia.

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.