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Rizzo, Adriana Antonieta do Nascimento, and Leila Trevizan Braz. "Divergência genética entre cinco genótipos de melão rendilhado." Horticultura Brasileira 20, no. 2 (June 2002): 171–73. http://dx.doi.org/10.1590/s0102-05362002000200010.
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Estimou-se a divergência genética entre cinco genótipos de melão rendilhado (Cucumis melo var. reticulatus Naud.) (JAB-20, JAB-21, JAB-22, JAB-23 e 'Bônus nº 2') e determinou-se qual a contribuição relativa das 16 características avaliadas [nº médio de flores masculinas, hermafroditas/planta; produção total de frutos/m², peso médio dos frutos comerciáveis; diâmetro médio transversal e longitudinal do fruto (DMTF e DMLF); diâmetro médio transversal da inserção do pedúculo (DMTP); espessura média do mesocarpo e epicarpo (EMM e EME); diâmetro médio longitudinal e transversal do lóculo (DMTL e DMLL); proporção da cavidade (PC); desprendimento de sementes (DS); teor de sólidos solúveis totais (SST), pH e acidez titulável (AT)] na divergência genética. Obtiveram-se dois grupos de similaridade: I- JAB-20, JAB-21 e 'Bônus nº2' e II- JAB-22 e JAB-23. As características DMLF, DMTP, DMLL, DS e SST foram as que mais contribuíram para a divergência genética entre os genótipos.
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Mary Sindhuja, N. M., and S. Kanthamani. "Three-Bit DMTL Phase Shifter for Phased Array Antennas." Journal of Circuits, Systems and Computers 28, no. 07 (June 27, 2019): 1950112. http://dx.doi.org/10.1142/s0218126619501123.
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RF MEMS phase shifter is a device that is used to modify the transmission phase of RF signal and provide signal control. Phase shifters are high-value components used in phased array antenna architectures. In phased array antenna the phase shifter is used to provide reliable electronic beam steering. The proposed 3-bit distributed MEMS transmission line (DMTL) phase shifter is designed using elevated coplanar waveguide (ECPW) transmission line for the first time, which results in better return loss of [Formula: see text]14.23[Formula: see text]dB and an average insertion loss of [Formula: see text]1.46[Formula: see text]dB. This paper discusses the development of ECPW-based 3-bit DMTL phase shifter designed to operate at 15[Formula: see text]GHz.
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Pandey, Shilpi, Deepak Bansal, Maninder Kaur, K. J. Rangra, and Seema Verma. "Compact 4-Bit DMTL Phase Shifter for KuBand Applications." INROADS- An International Journal of Jaipur National University 5, no. 1s (2016): 67. http://dx.doi.org/10.5958/2277-4912.2016.00014.x.
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Afrang, Saeid. "Small size and low loss resonator type DMTL phase shifter." Microelectronics Journal 44, no. 5 (May 2013): 442–53. http://dx.doi.org/10.1016/j.mejo.2013.02.014.
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Deng, Cheng, Jingfu Bao, Yijia Du, and Xinghai Zhao. "A novel DMTL capacitive switch with electrostatic actuation MAM capacitors." Microsystem Technologies 18, no. 5 (March 22, 2012): 537–41. http://dx.doi.org/10.1007/s00542-012-1467-3.
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Teymoori, Mir Majid, Massoud Dousti, and Saeid Afrang. "A low‐loss compact six‐bit DMTL phase shifter for phased array antenna applications." International Journal of Circuit Theory and Applications 48, no. 12 (September 24, 2020): 2111–29. http://dx.doi.org/10.1002/cta.2871.
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Saijets, Jan, Pekka Rantakari, and Tauno Vähä-Heikkilä. "Low loss KU- to KA-band analog DMTL phase shifter with 360° phase shift." Microwave and Optical Technology Letters 59, no. 6 (March 30, 2017): 1401–4. http://dx.doi.org/10.1002/mop.30543.
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Pandey, Shilpi, Deepak Bansal, Prachi Jhanwar, Seema Verma, and K. J. Rangra. "Design of Reliable Analog DMTL Phase Shifter with Improved Performance for Ku Band Applications." Defence Science Journal 65, no. 5 (September 11, 2015): 403. http://dx.doi.org/10.14429/dsj.65.8377.
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<p>An analog phase shifter based on distributed MEMS transmission line (DMTL) is designed for Ku band applications. Traditional RF MEMS phase shifter comprising 6 switches has limited phase shift of 37.75° due to instability region. A new concept of stopper is incorporated to achieve high phase shift. In the present paper, optimisation of the analog phase shifter is done to increase its phase shift upto 88.63°. Phase shift is a strong function of capacitance ratio which is increased from 1.75 to 2.95. The maximum operating voltage and mechanical resonant frequency for the phase shifter are 16 V and 8.3 KHz, respectively. The switching time is calculated to 56 μs. The simulated insertion loss of the phase shifter is -1.75 dB with return loss of -20.49 dB at 17 GHz. The simulated results are verified with analytical modelling which are in close match.</p>
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Garbulewski, Kazimierz, Stanisław Żakowicz, Simon Rabarijoely, and Anna Łada. "Sask method for testing hydraulic conductivity of soils by flat dilatometer (dmt)." Studia Geotechnica et Mechanica 34, no. 3 (October 1, 2012): 63–72. http://dx.doi.org/10.2478/sgm031205.
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Abstract DMT is one of the most popular methods of determining soil parameters needed to design a safe construction. Apart from the basic outcome parameter obtained from DMT measurements hydraulic conductivity (k) can be determined, previously proposed DMTA and DMTC methods were modified. The basic idea of the method is that the return of the deformed membrane is due to soil and water pressure. In the proposed SASK method the hydraulic conductivity of the soil is determined by measuring time-varying pressures A and C. Research has been performed at the experimental site of the Department of Geotechnical Engineering, WULS. In the paper, the assumptions of the new method for determining the hydraulic conductivity k are presented. The proposed method allows us to determine a reliable value for the hydraulic conductivity of clay soils. Using this method, the value of hydraulic conductivity (k = 5,47*10-11) is similar to the results of BAT, DMTA and laboratory measurements.
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Afrang, Saied, Keyvan Samandari, and Ghader Rezazadeh. "A small size Ka band six-bit DMTL phase shifter using new design of MEMS switch." Microsystem Technologies 23, no. 6 (June 3, 2016): 1853–66. http://dx.doi.org/10.1007/s00542-016-2987-z.
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Rolim, Luiz Clemente, João Roberto de Sá, Antonio Roberto Chacra, and Sérgio Atala Dib. "Heterogeneidade clínica e coexistência das neuropatias diabéticas: diferenças e semelhanças entre diabetes melito tipos 1 e 2." Arquivos Brasileiros de Endocrinologia & Metabologia 53, no. 7 (October 2009): 818–24. http://dx.doi.org/10.1590/s0004-27302009000700005.
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OBJETIVO: Estudar a heterogeneidade e a coexistência das neuropatias no diabetes melito tipos 1 (DMT1) e 2 (DMT2). MÉTODOS: Foram avaliados 74 DMT2 e 20 DMT1 em relação à idade (anos), tempo de diagnóstico do DM (TDDM, em anos), índice de massa corpórea (IMC, kg/m²), HbA1c e tipo de neuropatia (critérios da American Diabetes Association). RESULTADOS: DMT1 era mais jovem (32,7 ± 11 versus 56,9 ± 10,3; p = 0,0001), com maior TDDM (17,1 ± 9,7 versus 10,4 ± 6,8; p = 0,003) e menor IMC (23,6 ± 3,8 versus 28,4 ± 5,3; p = 0,0005). A neuropatia autonômica cardiovascular (NAC) (60% versus 32,4%; p = 0,02) e a coexistência desta com polineuropatia (PND) (62,5% versus 33,3%; p = 0,03) foram mais prevalentes no DMT1; a PND dolorosa crônica (PNDDC) (60,8% versus 30,0%; p = 0,009) o foi no DMT2. A HbA1c (p = 0,04) foi preditiva de PND em ambos os grupos. O TDDM (p = 0,03) e a PNDDC (p = 0,003) foram preditivos de NAC no DMT1. A idade (p = 0,0004) teve valor preditivo para PNDDC no DMT2. CONCLUSÕES: As neuropatias apresentam distribuição heterogênea no DMT1 e no DMT2. Com exceção do controle glicêmico, os fatores relacionados a essa complicação diferem de acordo com o tipo de diabetes.
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Osorio-Concepción, Macario, Carlos Lax, Eusebio Navarro, Francisco E. Nicolás, and Victoriano Garre. "DNA Methylation on N6-Adenine Regulates the Hyphal Development during Dimorphism in the Early-Diverging Fungus Mucor lusitanicus." Journal of Fungi 7, no. 9 (September 8, 2021): 738. http://dx.doi.org/10.3390/jof7090738.
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The epigenetic modifications control the pathogenicity of human pathogenic fungi, which have been poorly studied in Mucorales, causative agents of mucormycosis. This order belongs to a group referred to as early-diverging fungi that are characterized by high levels of N6-methyldeoxy adenine (6mA) in their genome with dense 6mA clusters associated with actively expressed genes. AlkB enzymes can act as demethylases of 6mA in DNA, with the most remarkable eukaryotic examples being mammalian ALKBH1 and Caenorhabditis elegans NMAD-1. The Mucor lusitanicus (formerly M. circinelloides f. lusitanicus) genome contains one gene, dmt1, and two genes, dmt2 and dmt3, encoding proteins similar to C. elegans NMAD-1 and ALKBH1, respectively. The function of these three genes was analyzed by the generation of single and double deletion mutants for each gene. Multiple processes were studied in the mutants, but defects were only found in single and double deletion mutants for dmt1. In contrast to the wild-type strain, dmt1 mutants showed an increase in 6mA levels during the dimorphic transition, suggesting that 6mA is associated with dimorphism in M. lusitanicus. Furthermore, the spores of dmt1 mutants challenged with macrophages underwent a reduction in polar growth, suggesting that 6mA also has a role during the spore–macrophage interaction that could be important in the infection process.
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G, Srihari, and Shanmuganantham T. "Design and Simulation of 5-Bit DMTL Phase Shifter with Improved RF Switch Incorporation of Stress Regions." HELIX 10, no. 4 (August 31, 2020): 66–75. http://dx.doi.org/10.29042/2020-10-4-66-75.
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Rabarijoely, Simon. "A New Method for the Estimation of Hydraulic Permeability, Coefficient of Consolidation, and Soil Fraction Based on the Dilatometer Tests (DMT)." Studia Geotechnica et Mechanica 41, no. 4 (December 30, 2019): 212–22. http://dx.doi.org/10.2478/sgem-2019-0021.
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AbstractThe main issue of the paper is the estimation of soil hydraulic permeability based on the DMT test. DMTA, DMTC and SASK methods performed in the Nielisz dam, Stegny and the SGGW Campus of the Warsaw University of Life Sciences sites are described. The article presents the implementation of the dilatometer Marchetti test (DMT) in the determination of soil fraction and effects of its occurrence in the subsoil, tested in the Nielisz dam located in the Wieprz river valley in the Lublin province, and in various sites in Warsaw (Stegny site and SGGW Campus of the Warsaw University of Life Sciences). In order to acquire the needed data, the flat dilatometer test (DMT) method was used. A direct and indirect pressure methodology of interpreting soil swelling was characterized in the article. The paper shows the possibilities of determining sand, silt and clay soil fractions based on po and p1 pressures from dilatometer tests (DMT) and the effective (σ’vo) and total (σvo) vertical in situ overburden stress. Additionally, the main advantage of this paper is the proposal of use of a new chart to determine hydraulic permeability and soil fraction, based on DMT tests.
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Dey, Sukomal, Shiban K. Koul, Ajay K. Poddar, and Ulrich L. Rohde. "Ku to V-band 4-bit MEMS phase shifter bank using high isolation SP4T switches and DMTL structures." Journal of Micromechanics and Microengineering 27, no. 10 (September 13, 2017): 105010. http://dx.doi.org/10.1088/1361-6439/aa8071.
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Sharma, Anesh K., Ashu K. Gautam, D. V. K. Sastry, and S. G. Singh. "Design & Modeling of 6-Bit Low Loss Ka Band Distributed MEMS Phase Shifter on GaAs." Advanced Materials Research 403-408 (November 2011): 4179–83. http://dx.doi.org/10.4028/www.scientific.net/amr.403-408.4179.
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This paper presents the design & modeling of distributed MEMS phase shifter for Ka band RF systems. The phase shift can be achieved by periodically placing the MEMS bridge variable capacitors as per Bragg frequency criteria on coplanar waveguide (CPW) using GaAs substrate. The EM & electromechanical simulation are carried out with various structural parameters to optimize the designs. The novelties like low insertion loss, low actuation voltage with distributed actuation pads & separate DC and RF are used to make the design unique. The EM simulations are carried out with HFSS and an insertion loss of -3.49 dB at 36GHz for a total Phase shift of 360 deg. was achieved with return loss of - 20.6 dB over a frequency band 34-38 GHz. The electromechanical simulations are carried to achieve the low actuation voltage of 10.3V. The significance of this study is the realization of the digital phase shifter through DMTL approach.
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Ganeva, S., K. Todorova, Ts Lukanov, G. Rayanova, and S. Blajeva. "Levels of Lymphocyte Subpopulations in Peripheral Blood among Patients with Diabetes." Acta Medica Bulgarica 48, no. 1 (April 1, 2021): 75–80. http://dx.doi.org/10.2478/amb-2021-0012.
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Abstract The aim of the study was to investigate the lymphocyte (lymph) subpopulations in peripheral blood as a part of the immune response among patients with diabetes mellitus type 1 (DMT1) and diabetes mellitus type 2 (DMT2). Patients and methods: A prospective, cross-sectional, comparative, “case-control” study was conducted among 22 patients with DMT1 and 70 patients with DMT2. The levels of lymph subtypes [general nonspecific T-lymph (CD3+); T-helper lymph (CD4+); T-cytotoxic lymph (CD8+), natural killers [NK cells (CD3\ CD16+/CD56)] and B-lymph (CD19+)] in blood was measured and compared by flow-cytometric analisys (FAC Sort, BD). Results were compared to those of 21 healthy persons. The data was processed using the statistics software. Results: Patients with DMT1 had longer duration of the disease, compared to patients with DMT2. No significant differences between arterial blood pressure, НвА1с levels and lipid profile among the patients with DMT1 and DMT2 were present. There were no differences in the total leukocyte count between the groups (DMT1-6,91 ± 1,32.109/l; DMT2-7,28 ± 1,85.109/l; controls-6,89 ± 1,07.109/l). The results from the flowcytometric investigation showed significantly higher absolute number of T-all lymph (CD3+), Th lymph (CD4+) and all NK (CD3\ CD16+/CD56), as well as a lower absolute number of Ts (CD8+) and B (CD19+) lymph among the diabetic patients compared to healthy subjects. The Th/Ts ratio in patients with DMT1 (2,02 ± 0,44) and DMT2 (2,36 ± 0,37) was also significantly higher compared to ratio of controls (1,02 ± 0,06). No significant differences were noted in the lymph subpopulations between the two groups with DM. Conclusions: Changes of lymph types in peripheral blood in diabetic patients demonstrate immune activation and dysregulation among the two types of diabetes.
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Marriott, James J., Muhammad Mamdani, Gustavo Saposnik, Tara Gomes, Michael Manno, and Paul W. O'Connor. "Multiple Sclerosis Disease-Modifying Therapy Prescribing Patterns in Ontario." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 40, no. 1 (January 2013): 67–72. http://dx.doi.org/10.1017/s031716710001297x.
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Abstract:Background:Differences in Multiple sclerosis (MS) disease-modifying therapy (DMT) prescribing patterns between different groups of neurologists have not been explored.Objective:To examine concentrations of prescribing patterns and to assess if MS-specialists use a broader range of DMTs relative to general neurologists.Methods:We conducted a cross-sectional study using administrative claims databases in Ontario, Canada to link neurologists to 2009 DMT prescription data. MS specialization was defined using both practice location and prescription patterns. Lorenz curves and Gini coefficients were constructed to examine prescribing patterns, separating neurologist characteristics dichotomously and separating Avonex from the other standard DMTs (Betaseron, Rebif and Copaxone). Gini coefficient 95% confidence intervals (CIs) were derived using jack-knife statistical techniques.Results:Prescriptions were highly concentrated with 12% of Ontario neurologists prescribing 80% of DMTs. There was a trend towards Avonex being more commonly prescribed relative to the other DMTs. When MS specialization was defined by DMT prescribing, high-volume prescribing neurologists showed a broader range of DMT prescribing (Gini 0.38-0.44) in comparison to low-volume prescribers (Gini 0.57-0.66).Conclusions:The majority of DMTs are prescribed by a small subset of neurologists. High-volume prescribing MS-specialists show more variability in DMT use while low-volume prescribers tend to individually focus on a narrower range of DMTs.
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Wijnands, José Maria Andreas, Feng Zhu, Elaine Kingwell, John David Fisk, Charity Evans, Ruth Ann Marrie, Yinshan Zhao, and Helen Tremlett. "Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 10 (March 30, 2018): 1050–56. http://dx.doi.org/10.1136/jnnp-2017-317493.
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ObjectiveLittle is known about disease-modifying treatments (DMTs) for multiple sclerosis (MS) and infection risk in clinical practice. We examined the association between DMTs and infection-related medical encounters.MethodsUsing population-based administrative data from British Columbia, Canada, we identified MS cases and followed them from their first demyelinating event (1996–2013) until emigration, death or study end (December 2013). Associations between DMT exposure (by DMT generation or class) and infection-related physician or hospital claims were assessed using recurrent time-to-events models, adjusted for age, sex, socioeconomic status, index year and comorbidity count. Results were reported as adjusted HRs (aHRs).ResultsOf 6793 MS cases, followed for 8.5 years (mean), 1716 (25.3%) were DMT exposed. Relative to no DMT, exposure to any first-generation DMT (beta-interferon or glatiramer acetate) was not associated with infection-related physician claims (aHR: 0.96; 95% CI 0.89 to 1.02), nor was exposure to these drug classes when assessed separately. Exposure to any second-generation DMT (oral DMT or natalizumab) was associated with an increased hazard of an infection-related physician claim (aHR: 1.47; 95% CI 1.16 to 1.85); when assessed individually, the association was significant for natalizumab (aHR: 1.59; 95% CI 1.19 to 2.11) but not the oral DMTs (aHR: 1.17; 95% CI 0.88 to 1.56). While no DMTs were associated with infection-related hospital claims, these hospitalisations were also uncommon.ConclusionExposure to first-generation DMTs was not associated with an altered infection risk. However, exposure to the second-generation DMTs was, with natalizumab associated with a 59% increased risk of an infection-related physician claim. Continued pharmacovigilance is warranted, including an investigation of the DMT-associated infection burden on patient outcomes.
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Sotirchos, Elias S., Natalia Gonzalez-Caldito, Blake E. Dewey, Kathryn C. Fitzgerald, Jeffrey Glaister, Angeliki Filippatou, Esther Ogbuokiri, et al. "Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis." Multiple Sclerosis Journal 26, no. 3 (February 11, 2019): 312–21. http://dx.doi.org/10.1177/1352458519826364.
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Background: The effects of disease-modifying therapies (DMTs) on region-specific brain atrophy in multiple sclerosis (MS) are unclear. Objective: To determine the effects of higher versus lower efficacy DMTs on rates of brain substructure atrophy in MS. Methods: A non-randomized, observational cohort of people with MS followed with annual brain magnetic resonance imaging (MRI) was evaluated retrospectively. Whole brain, subcortical gray matter (GM), cortical GM, and cerebral white matter (WM) volume fractions were obtained. DMTs were categorized as higher (DMT-H: natalizumab and rituximab) or lower (DMT-L: interferon-beta and glatiramer acetate) efficacy. Follow-up epochs were analyzed if participants had been on a DMT for ⩾6 months prior to baseline and had at least one follow-up MRI while on DMTs in the same category. Results: A total of 86 DMT epochs (DMT-H: n = 32; DMT-L: n = 54) from 78 participants fulfilled the study inclusion criteria. Mean follow-up was 2.4 years. Annualized rates of thalamic (−0.15% vs −0.81%; p = 0.001) and putaminal (−0.27% vs −0.73%; p = 0.001) atrophy were slower during DMT-H compared to DMT-L epochs. These results remained significant in multivariate analyses including demographics, clinical characteristics, and T2 lesion volume. Conclusion: DMT-H treatment may be associated with slower rates of subcortical GM atrophy, especially of the thalamus and putamen. Thalamic and putaminal volumes are promising imaging biomarkers in MS.
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Banks, Andrae, Lashawnda Fields, Curtis O’Dwyer, Marquisha Lawrence Scott, and Sean Joe. "Treating Mental Illness Among Diabetic Black Male Adolescents." Research on Social Work Practice 28, no. 3 (April 12, 2017): 330–39. http://dx.doi.org/10.1177/1049731517702746.
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Objective: To examine randomized controlled trials (RCTs) for treatment evidence for Black male adolescents suffering from comorbid mental illness and diabetes mellitus. Method: A review of the studies published in English-language journals was conducted. Results: We found no RCT focused on Black males with diabetes mellitus Type 2 (DMT2). However, we found RCT inclusive of Black male adolescents with diabetes mellitus Type 1 (DMT1). Multisystemic therapy appears to be the best supported overall treatment for DMT1 management and psychosocial functioning followed by an enhanced form of behavioral family systems therapy for diabetics. Metformin was the only treatment in this review noted for use within DMT2. Metformin and a nursing-based telephone case management intervention realized utility as secondary services. Conclusions: There are gaps present for what effectively treats comorbid mental illness and DMT2 in Black male adolescents. For comorbid mental illness and DMT1, there are gaps in additional efficacious treatments, effectiveness across conditions, and effect duration beyond 24 months.
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Rae-Grant, Alexander, Gregory S. Day, Ruth Ann Marrie, Alejandro Rabinstein, Bruce A. C. Cree, Gary S. Gronseth, Michael Haboubi, et al. "Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis." Neurology 90, no. 17 (April 23, 2018): 777–88. http://dx.doi.org/10.1212/wnl.0000000000005347.
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ObjectiveTo develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS).MethodsA multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine–compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus–based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence.ResultsThirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.
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Dey, Sukomal, and Shiban K. Koul. "Design, development and characterization of an x-band 5 bit DMTL phase shifter using an inline MEMS bridge and MAM capacitors." Journal of Micromechanics and Microengineering 24, no. 9 (July 31, 2014): 095007. http://dx.doi.org/10.1088/0960-1317/24/9/095007.
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Cvetković, Tatjana, Predrag Vlahović, Vidosava đorđević, Lilika Zvezdanović, Dušica Pavlović, Gordana Kocić, and Dušan Sokolović. "The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy." Journal of Medical Biochemistry 27, no. 3 (July 1, 2008): 376–82. http://dx.doi.org/10.2478/v10011-008-0019-y.
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The Significance of Urinary Markers in the Evaluation of Diabetic Nephropathy Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications, including nephropathy (DN). The aim of this study was to determine the parameters of oxidative injury of lipids and proteins as well as the activity of ectoenzymes in the urine of DN patients. The study included 40 individuals: 10 patients with type 2 diabetes mellitus and microalbuminuria (DMT2-MIA), 10 type 2 diabetic patients with macroalbuminuria (DMT2-MAA), 10 patients with type 1 diabetes and microalbuminuria (DMT1-MIA) and 10 age- and sex-matched healthy subjects (control). In the urine we determined TBA reactive substances (TBARS), reactive carbonyl groups (RCG), and the activity of ectoenzymes N-acetyl-β-d-glucosaminidase (NAG), plasma cell differentiation antigen (PC-1), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV). A higher concentration of TBARS in the urine was found in DMT2-MIA and DMT1-MIA, compared to the control group (p<0.001 and P<0.05). The urine concentration of RCD shows similar results with a significant elevation in the groups with DMT2-MAA and DMT1-MIA, compared to the DMT2-MIA (p<0.001) and control group (p<0.001). Activities of NAG, APN and DPPIV were significantly higher in the urine of DMT2-MAA, compared to the control (p<0.01). The activity of PC-1 was slightly increased in that group, but not significantly. In conclusion, the level of oxidative stress markers and activities of brush border ectoenzymes in the urine may be a useful non-invasive and easily repeatable test in DN.
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Hartung, Daniel M. "Health economics of disease-modifying therapy for multiple sclerosis in the United States." Therapeutic Advances in Neurological Disorders 14 (January 2021): 175628642098703. http://dx.doi.org/10.1177/1756286420987031.
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Multiple sclerosis (MS) is chronic neuroinflammatory condition associated with significant disability. The economic burden of MS is substantial, and high and rising disease-modifying therapy (DMT) prices are the single largest drivers of healthcare expenditures. Over much of the last decade, price increases for most DMTs have surpassed 10% annually. Currently, many MS DMTs exceed US$90,000 a year and their economic value is widely debated. In addition to creating a financial burden for the healthcare system, high DMT costs negatively impact patients through unaffordable out-of-pocket costs and excessive restrictions by insurance companies. The objective of this narrative review is to summarize economic issues related to MS DMTs, including trends in pricing, relative value, and effects on patient care in the United States.
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Zhang, Yinan, Natalia Gonzalez Caldito, Afsaneh Shirani, Amber Salter, Gary Cutter, William Culpepper, Mitchell Wallin, et al. "Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials." Therapeutic Advances in Neurological Disorders 13 (January 2020): 175628642096901. http://dx.doi.org/10.1177/1756286420969016.
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Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.
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Mäurer, Mathias, Klaus Tiel-Wilck, Eckard Oehm, Nils Richter, Michael Springer, Patrick Oschmann, Arndt Manzel, et al. "Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis." Therapeutic Advances in Neurological Disorders 12 (January 2019): 175628641989207. http://dx.doi.org/10.1177/1756286419892077.
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Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014–2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman’s wish to become pregnant. Expectations of the new DMT and patients’ assessment of the decision maker were also recorded. Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.
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Krysko, Kristen M., Jennifer Graves, Mary Rensel, Bianca Weinstock-Guttman, Gregory Aaen, Leslie Benson, Tanuja Chitnis, et al. "Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US." Neurology 91, no. 19 (October 17, 2018): e1778-e1787. http://dx.doi.org/10.1212/wnl.0000000000006471.
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ObjectiveTo characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age.MethodsThis is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005.ResultsAs of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults.ConclusionNewer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.
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Al-Sakran, Lina, Ruth Ann Marrie, David Blackburn, Katherine Knox, and Charity Evans. "Association between disease-modifying therapies for multiple sclerosis and healthcare utilisation on a population level: a retrospective cohort study." BMJ Open 9, no. 11 (November 2019): e033599. http://dx.doi.org/10.1136/bmjopen-2019-033599.
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ObjectiveDisease-modifying therapy (DMT) use in multiple sclerosis (MS) has increased significantly. However, the impact of DMTs on healthcare use is limited and conflicting, and rarely examined at a population level. This study examined the association between DMTs and healthcare utilisation at the population level.DesignRetrospective cohort.SettingHealth administrative data from Saskatchewan, Canada (1997–2016).ParticipantsTo test for associations at the population level, we identified two cohorts. The general population cohort included all Saskatchewan residents ≥18 years who were drug plan beneficiaries. The MS cohort included individuals ≥18 years, identified using a validated definition (≥3 hospital, physician or drug claims for MS).Main outcome measures and methodsTo test for an association between the total number of DMT dispensations per year and the total number of hospitalisations we used negative binomial regression fitted with generalised estimating equations (GEE); only hospitalisations that occurred after the date of MS diagnosis (date of first claim for MS or demyelinating disease) were extracted. To test for an association between the number of DMT dispensations and physician claims, negative binomial distributions with GEE were fit as above. Results were reported as rate ratios (RR), with 95% CIs, and calculated for every 1000 DMT dispensations.ResultsThe number of DMT dispensations was associated with a decreased risk for all-cause (RR=0.994; 95% CI 0.992 to 0.996) and MS-specific (RR=0.909; 95% CI 0.880 to 0.938) hospitalisations. The number of DMT dispensations was not associated with the number of all-cause (RR=1.006; 95% CI 0.990 to 1.022) or MS-specific (RR=0.962; 95% CI 0.910 to 1.016) physician claims.ConclusionIncreased DMT use in Saskatchewan was associated with a reduction in hospitalisations, but did not impact the number of physician services used. Additional research on cost-benefit and differing treatment strategies would provide further insight into the true impact of DMTs on healthcare utilisation at a population level.
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McFaul, Derek, Nektar N. Hakopian, Jessica B. Smith, Allen Scott Nielsen, and Annette Langer-Gould. "Defining Benign/Burnt-Out MS and Discontinuing Disease-Modifying Therapies." Neurology - Neuroimmunology Neuroinflammation 8, no. 2 (February 8, 2021): e960. http://dx.doi.org/10.1212/nxi.0000000000000960.
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ObjectiveTo determine whether MS disease-modifying therapies (DMTs) can be safely discontinued in patients aged 50 years or older with suspected benign/burnt-out MS and to define criteria to identify such patients.MethodsWe conducted a retrospective cohort study of 136 patients with suspected benign/burnt-out MS who discontinued DMTs from the electronic health record (EHR) at Kaiser Permanente Southern California.ResultsThe majority discontinued an injectable DMT (n = 131, 96%). At the time of DMT discontinuation, mean and SD for age was 60.6 (6.2) years, disease duration 19.5 (10.7) years, and time since last relapse 11.0 (7.2) years. After a mean duration of follow-up of 5.0 years post-DMT discontinuation, 5 (3.7%) patients had a relapse, 2 (1.5%) had mild residual deficits, and 3 (2.2%) had asymptomatic MRI disease activity. Patients with MS disease activity following DMT discontinuation were younger (median = 53.6 years) than those who remained disease activity free. Fifty patients (36.8%) had only 1 lifetime relapse, of whom 1 relapsed post-DMT discontinuation. Sixty (56.6%) of 106 patients with spinal cord MRIs before discontinuation showed demyelinating lesions.ConclusionsDMT discontinuation in older patients with suspected benign/burnt-out MS appears safe. Our findings suggest that MRI evidence of spinal cord involvement does not preclude the possibility of benign/burnt-out MS, and for those with 2 or more lifetime relapses, a benign/burn-out classification is best reserved for those aged 55 years and older. Future studies to determine whether DMT discontinuation is safe at a younger age in patients with a single lifetime relapse are needed.Classification of EvidenceThe study provides Class IV evidence that DMTs can be safely discontinued in older patients with suspected benign/burnt-out MS.
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Hardianto, Dudi. "TELAAH KOMPREHENSIF DIABETES MELITUS: KLASIFIKASI, GEJALA, DIAGNOSIS, PENCEGAHAN, DAN PENGOBATAN." Jurnal Bioteknologi & Biosains Indonesia (JBBI) 7, no. 2 (January 14, 2021): 304–17. http://dx.doi.org/10.29122/jbbi.v7i2.4209.
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Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. In general, diabetes is classified into type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational, and other specific diabetes. The causes of diabetes are genetic disorders and environmental. Common symptoms of diabetes include: polydipsia, polyphagia, glycosuria, polyuria, dehydration, fatigue, weight loss, reduced vision, cramps, constipation, and candida infection. Test for diagnosis of diabetes include: fasting plasma glucose test, plasma glucose test after 2 hours of 75 g oral glucose administration, the glycated hemoglobin test (HbA1C), and random blood glucose test. Prevention of T1DM is still difficult because of the limited knowledge of metabolic, genetic, and immunological processes in the development of T1DM. T2DM is prevented by lifestyle and medical intervention. Insulin is the only drug for T1DM, whereas T2DM is treated with metformin as drug’s primary choice for reducing blood glucose levels. Diabetes melitus merupakan penyakit kelainan metabolisme yang ditandai dengan hiperglikemia. Secara umum, diabetes diklasifikasikan menjadi: diabetes melitus tipe 1 (DMT1), diabetes melitus tipe 2 (DMT2), gestasional, dan diabetes spesifik lain. Penyebab diabetes adalah kelainan genetik dan lingkungan. Gejala umum diabetes antara lain: polidipsia, polifagia, glikosuria, poliuria, dehidrasi, kelelahan, penurunan berat badan, daya penglihatan berkurang, kram, konstipasi, dan infeksi candida. Pemeriksaaan untuk diagnosis diabetes meliputi: pemeriksaan glukosa plasma saat puasa, pemeriksaan glukosa plasma setelah 2 jam pemberian glukosa oral 75 g, pemeriksaan hemoglobin terglikasi (HbA1C), dan pemeriksaan glukosa darah acak. Pencegahan DMT1 masih sulit karena terbatasnya pengetahuan proses metabolisme, genetik, dan imunologi pada perkembangan DMT1. DMT2 dicegah dengan intervensi gaya hidup dan intervensi medis. Insulin merupakan satu-satunya obat untuk DMT1, sedangkan DMT2 diobati dengan metformin sebagai pilihan utama dan non obat untuk menurunkan kadar glukosa dalam darah.
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Knox, Katherine B., Aman Saini, and Michael C. Levin. "The Dilemma of When to Stop Disease-Modifying Therapy in Multiple Sclerosis." International Journal of MS Care 22, no. 2 (March 1, 2020): 75–84. http://dx.doi.org/10.7224/1537-2073.2018-107.
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Abstract Background: Disease-modifying therapy (DMT) has changed the landscape of multiple sclerosis (MS) care. However, there is lack of consensus on the duration of treatment and the selection of individuals most likely to benefit from continued treatment. Current evidence, practice guidelines, health policy, and ethical considerations presented together may further inform challenging clinical decision making and future directions. The objectives of this study were to conduct a narrative review of original research and practice guideline recommendations on discontinuation of DMTs in MS; to collect information regarding Canadian regional reimbursement policies for DMT coverage in MS; and to present ethical considerations applicable to such decision making. Methods: A literature review was conducted of the MEDLINE/PubMed, OneFile (GALE), Scopus (Elsevier), and ProQuest Biological Science Collection databases. Data regarding Canadian regional reimbursement policies for DMT coverage in MS were collected from the ministry/government websites. Ethical considerations were reviewed in the context of the identified evidence, guidelines, and policies. Results: The literature lacks evidence from prospective randomized controlled trials that directly addresses the issue of discontinuation of DMTs in MS. Current practice guidelines advocate the vital role of patient choice in decision making. There are regional variations in Expanded Disability Status Scale criteria scores for continuing MS DMT coverage among Canadian provinces/territories. Conclusions: In the absence of strong evidence on discontinuation of DMTs, shared decision making and consideration of the ethical complexities could help in the decision-making process.
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Mirsky, Matthew M., Ruth Ann Marrie, and Alexander Rae-Grant. "Antidepressant Drug Treatment in Association with Multiple Sclerosis Disease-Modifying Therapy." International Journal of MS Care 18, no. 6 (November 1, 2016): 305–10. http://dx.doi.org/10.7224/1537-2073.2016-056.
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Background: The Explorys Enterprise Performance Management (EPM) database contains de-identified clinical data for 50 million patients. Multiple sclerosis (MS) disease-modifying therapies (DMTs), specifically interferon beta (IFNβ) treatments, may potentiate depression. Conflicting data have emerged, and a large-scale claims-based study by Patten et al. did not support such an association. This study compares the results of Patten et al. with those using the EPM database. Methods: “Power searches” were built to test the relationship between antidepressant drug use and DMT in the MS population. Searches were built to produce a cohort of individuals diagnosed as having MS in the past 3 years taking a specific DMT who were then given any antidepressant drug. The antidepressant drug therapy prevalence was tested in the MS population on the following DMTs: IFNβ-1a, IFNβ-1b, combined IFNβ, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate. Results: In patients with MS, the rate of antidepressant drug use in those receiving DMTs was 40.60% to 44.57%. The rate of antidepressant drug use for combined IFNβ DMTs was 41.61% (males: 31.25%–39.62%; females: 43.10%–47.33%). Antidepressant drug use peaked in the group aged 45 to 54 years for five of six DMTs. Conclusions: We found no association between IFNβ treatment and antidepressant drug use in the MS population compared with other DMTs. The EPM database has been validated against the Patten et al. data for future use in the MS population.
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Dey, Sukomal, Shiban Koul, Ajay Poddar, and Ulrich Rohde. "Corrigendum: Ku to V-band 4-bit MEMS phase shifter bank using high isolation SP4T switches and DMTL structures (2017 J. Micromech. Microeng. 27 105010)." Journal of Micromechanics and Microengineering 28, no. 2 (January 9, 2018): 029501. http://dx.doi.org/10.1088/1361-6439/aa9ebf.
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Jonker, Marcel F., Bas Donkers, Lucas M. A. Goossens, Renske J. Hoefman, Lea J. Jabbarian, Esther W. de Bekker-Grob, Matthijs M. Versteegh, Gerard Harty, and Schiffon L. Wong. "Summarizing Patient Preferences for the Competitive Landscape of Multiple Sclerosis Treatment Options." Medical Decision Making 40, no. 2 (February 2020): 198–211. http://dx.doi.org/10.1177/0272989x19897944.
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Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data ( n=799 and n=363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R2 estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients’ choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%–3%). Patient preferences were strongly correlated with patients’ MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients’ DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.
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Scutera, Sara, Tiziana Musso, Paola Cavalla, Giorgia Piersigilli, Rosaria Sparti, Sara Comini, Marco Vercellino, Anna Maria Cuffini, Giuliana Banche, and Valeria Allizond. "Inhibition of Human Neutrophil Functions In Vitro by Multiple Sclerosis Disease-Modifying Therapies." Journal of Clinical Medicine 9, no. 11 (November 2, 2020): 3542. http://dx.doi.org/10.3390/jcm9113542.
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There is a growing optimism about the potential of new disease-modifying therapies (DMTs) in the management of relapsing-remitting multiple sclerosis (RRMS) patients. However, this initial enthusiasm has been tempered by evidence indicating that multiple sclerosis (MS) patients undergoing DMT may be at higher risk of developing infections through incompletely understood mechanisms. As neutrophils provide the first line of defense against pathogens, here we have compared the effects of some of the commonly used MS DMTs (i.e., moderate-efficacy injective, first-line: interferonβ-1b (IFNβ-1b), glatiramer acetate (GA); and high-efficacy, second-line: fingolimod (FTY) and natalizumab (NAT)) on the in vitro viability and functions of neutrophils isolated from healthy subjects. All the DMTs tested impaired the ability of neutrophils to kill Klebsiella pneumoniae, whereas none of them affected the rate of neutrophil apoptosis or CD11b and CD62L cell surface expression. Intriguingly, only FTY exposure negatively affected K. pneumoniae-induced production of reactive oxygen species (ROS) in polymorphonuclear leukocytes (PMNs). Furthermore, neutrophils exposed to K. pneumoniae secreted enhanced amounts of CXCL8, IL-1β and TNF-α, which were differentially regulated following DMT pretreatment. Altogether, these findings suggest that DMTs may increase the susceptibility of MS patients to microbial infections, in part, through inhibition of neutrophil functions. In light of these data, we recommend that the design of personalized therapies for RRMS patients should take into account not just the mechanism of action of the chosen DMT but also the potential risk of infection associated with the administration of such therapeutic compounds to this highly vulnerable population.
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Ferguson, C. J., M. Wareing, D. T. Ward, R. Green, C. P. Smith, and D. Riccardi. "Cellular localization of divalent metal transporter DMT-1 in rat kidney." American Journal of Physiology-Renal Physiology 280, no. 5 (May 1, 2001): F803—F814. http://dx.doi.org/10.1152/ajprenal.2001.280.5.f803.
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We have demonstrated that the kidney plays an important role in iron balance and that metabolically significant reabsorption of this ion occurs in the loop of Henle and the collecting ducts [Wareing M, Ferguson CJ, Green R, Riccardi D, and Smith CP. J Physiol (Lond) 524: 581–586, 2000]. To test the possibility that the divalent metal transporter DMT1 (Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, and Hediger MA. Nature 388: 482–488, 1997) could represent the apical route for iron entry in the kidney, we raised and affinity-purified an anti-DMT-1 polyclonal antibody and determined DMT-1 distribution in rat kidney by Western analysis, immunofluorescence, and confocal microscopy. The strongest DMT1-specific (i.e., peptide-protectable) immunoreactivity was found in the collecting ducts, in both principal and intercalated cells. Thick ascending limbs of Henle's loop and, more intensely, distal convoluted tubules exhibited apical immunostaining. Considerable intracellular DMT-1 immunoreactivity was seen throughout the nephron, particularly in S3 segments. The described distribution of DMT-1 protein is in agreement with our previous identification of nephron sites of iron reabsorption, suggesting that DMT-1 provides the molecular mechanism for apical iron entry in the distal nephron but not in the proximal tubule. Basolateral iron exit may be facilitated by a different system.
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Guttman, Mark, Marco Pedrazzoli, Marina Ponomareva, Marsha Pelletier, Louisa Townson, Kopano Mukelabai, Aaron Levine, Anna-Lena Nordström, Ralf Reilmann, and Jean-Marc Burgunder. "The Impact of Upcoming Treatments in Huntington’s Disease: Resource Capacity Limitations and Access to Care Implications." Journal of Huntington's Disease 10, no. 2 (June 9, 2021): 303–11. http://dx.doi.org/10.3233/jhd-200462.
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Background: The most advanced disease-modifying therapies (DMTs) in development for Huntington’s disease (HD) require intrathecal (IT) administration, which may create or exacerbate bottlenecks in resource capacity. Objective: To understand the readiness of healthcare systems for intrathecally administered HD DMTs in terms of resource capacity dynamics and implications for patients’ access to treatment. Methods: Forty HD centres across 12 countries were included. Qualitative and quantitative data on current capacity in HD centres and anticipated capacity needs following availability of a DMT were gathered via interviews with healthcare professionals (HCPs). Data modelling was used to estimate the current capacity gap in HD centres. Results: From interviews with 218 HCPs, 25% of HD centres are estimated to have the three components required for IT administration (proceduralists, nurses and facilities). On average, 114 patients per centre per year are anticipated to receive intrathecally administered DMTs in the future. At current capacity, six of the sampled centres are estimated to be able to deliver DMTs to all the anticipated patients based on current resources. The estimated waiting time for IT administration at current capacity will average 60 months (5 years) by the second year after DMT availability. Conclusion: Additional resources are needed in HD centres for future DMTs to be accessible to all anticipated patients. Timely collaboration by the HD community will be needed to address capacity gaps. Healthcare policymakers and payers will need to address costs and navigate challenges arising from country- or region-specific healthcare delivery schemes.
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Meca-Lallana, José, Juan Antonio García-Merino, Sergio Martínez-Yélamos, Angela Vidal-Jordana, Lucienne Costa, Sara Eichau, Àlex Rovira, Luis Brieva, Eduardo Agüera, and Alfredo Rodríguez-Antigüedad Zarranz. "Identification of patients with relapsing multiple sclerosis eligible for high-efficacy therapies." Neurodegenerative Disease Management 11, no. 3 (June 2021): 251–61. http://dx.doi.org/10.2217/nmt-2020-0049.
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Relapsing multiple sclerosis (RMS) presents a highly variable clinical evolution among patients, and its management should be personalized. Although there is no cure at present, effective disease-modifying therapies (DMTs) are available. Selection of the most appropriate DMT for each patient is influenced by several clinical, radiological and demographic aspects as well as personal preferences that, at times, are not covered in the regulatory criteria. This may be a source of difficulty, especially in certain situations where so-called ‘high-efficacy DMTs’ (usually considered second-line) could be of greater benefit to the patient. In this narrative review, we discuss evidence and experience, and propose a pragmatic guidance on decision-making with respect to the indication and management of high-efficacy DMT in adult patients with RMS based on expert opinion.
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Delcoigne, Bénédicte, Ali Manouchehrinia, Christian Barro, Pascal Benkert, Zuzanna Michalak, Ludwig Kappos, David Leppert, et al. "Blood neurofilament light levels segregate treatment effects in multiple sclerosis." Neurology 94, no. 11 (February 11, 2020): e1201-e1212. http://dx.doi.org/10.1212/wnl.0000000000009097.
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ObjectiveTo determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).MethodsData including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).ResultsThe baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.ConclusionChoice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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Walker, Robert, Mark Schulz, Birendra Arora, Eric Chung, Prabhjot Juneja, Stephane Verhaeghe, Tim Spelman, and Simon Broadley. "057 Real world evidence (RWE) on long-term persistence of fingolimod in relapsing-remitting multiple sclerosis (RRMS) in australia." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 6 (May 24, 2018): A23.3—A24. http://dx.doi.org/10.1136/jnnp-2018-anzan.56.
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IntroductionThis study aimed to examine and compare patient persistence of fingolimod to all reimbursed disease modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) in Australia.MethodThe Pharmaceutical Benefits Scheme (PBS) 10% sample supplied by the Department of Human Services was used in this study. Eligible patients must have received a script for a reimbursed DMT for RRMS between September 2011 and February 2016. Patient demographics were summarised using mean and standard deviation or frequency percentage. Persistence was defined as a patient that remained on a DMT with a gap in scripts of no longer than 4 months. Individual patients could be included multiple times if they initiated a new DMT during the study period. Persistence was derived using the Kaplan-Meier method and hazard ratios (HR). Persistence to individual treatments was then compared to the average persistence observed across all treatments; p-values were based on the log-rank test.Results720 unique patients were eligible for the study, contributing 1827 observations that for analysis (2.5 new initiations/patient). Overall the median persistence (MP) to therapy was 29.6 months with 67.7% of patients remaining on therapy for 12 months. The only DMT with significantly better persistence compared to the overall average was fingolimod (HR 0.65 (95%CI 0.57–0.73; p<0.001). Patients had an MP of 60 months on fingolimod with 79.5% of patients persistent at 12 months. Patients were significantly less persistent to interferon Beta-1a, interferon Beta-1b, glatiramer acetate and dimethyl fumarate (hazard ratios above 1.27 (p values all≤0.001) whilst the remaining DMTs, teriflunomide and natalizumab, showed no significant difference from the average persistence.ConclusionIn this analysis of PBS sample data, patients were most persistent to fingolimod treatment amongst all DMTs.
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Gordon, Jessica M., Deidre Orriola, Mary Unangst, Federico Gordon, and Yazmin E. Rodriguez Vellon. "Lessons Learned from a Medical Response Team 45 Days Post Hurricane Maria in Puerto Rico." Disaster Medicine and Public Health Preparedness 14, no. 1 (July 15, 2019): 28–33. http://dx.doi.org/10.1017/dmp.2019.65.
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ABSTRACTObjective:Describe the lived experience of a grassroots, non-governmental disaster medical team (DMT) through a research lens and share practical lessons learned, based on the DMT’s experience to support and inform future response teams.Methods:Forty-five days after Hurricane Maria, a non-governmental DMT provided primary medical care via community based pop-up clinics and home visitations in 5 different areas of Puerto Rico. Observational data, photo images, and debriefing notes were collected and documented in the response team’s daily activity log. Field notes were coded using a descriptive coding method and then categorized into 2 domains specific to public health and medical diagnosis.Results:Medical aid was provided to nearly 300 (N = 296) residents. Field note observations identified exhaustion related to living conditions and the exacerbation of underlying conditions such as reactive airway diseases, diabetes, hypertension, and depression due to the compounding effects of multiple post-disaster triggers. During home visitations, feelings of sadness and helplessness were identified secondary to natural disaster trauma and current living conditions.Conclusion:Our non-governmental DMT displayed similar characteristics demonstrated by federal DMTs post natural disaster. A number of strategic lessons learned emerged from the public health intervention important to future non-governmental DMTs.
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Wu, Dunli, Yi Soong, Guo-Min Zhao, and Hazel H. Szeto. "A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning." American Journal of Physiology-Heart and Circulatory Physiology 283, no. 2 (August 1, 2002): H783—H791. http://dx.doi.org/10.1152/ajpheart.00193.2002.
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We recently discovered an opioid peptide analgesic, 2′,6′-dimethyltyrosine (Dmt)-d-Arg-Phe-Lys-NH2([Dmt1]DALDA), that can protect against ischemia-induced myocardial stunning. In buffer-perfused hearts, 30-min global ischemia followed by reperfusion resulted in a significant increase in norepinephrine (NE) overflow immediately upon reperfusion and significant decline in contractile force (45%). Pretreatment with [Dmt1]DALDA before ischemia completely abolished myocardial stunning and significantly reduced NE overflow (68%). In contrast, pretreatment with morphine before ischemia only provided brief protection against myocardial stunning and no reduction in NE overflow. [Dmt1]DALDA inhibited [3H]NE uptake into cardiac synaptosomes in vitro (IC50 = 3.9 μM), whereas morphine had no effect. Surprisingly, protection against myocardial stunning was apparent even when hearts were perfused with [Dmt1]DALDA only upon reperfusion, whereas reperfusion with morphine had no effect. Binding studies with [3H][Dmt1]DALDA revealed no high-affinity specific binding in cardiac membranes, suggesting that the cardioprotective actions of [Dmt1]DALDA are not mediated via opioid receptors. These findings suggest that [Dmt1]DALDA is a potent analgesic that may be useful for myocardial stunning resulting from cardiac interventions or myocardial ischemia.
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Johal, Tarneer Kaur. "The Effects of Multiple Sclerosis and Disease Modifying Therapy on Pregnancy." University of Ottawa Journal of Medicine 7, no. 2 (December 18, 2017): 42–47. http://dx.doi.org/10.18192/uojm.v7i1.1758.
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AbstractMultiple sclerosis (MS) is the most common inflammatory condition of the central nervous system. Disease modifying therapy (DMT) aims to reduce relapse rates and decrease the quantity of lesions in the brain and spinal cord. Since MS is more prevalent in women than men, it is important to be aware of the interplay between MS and pregnancy. As MS can engender sexual dysfunction, primarily in the form of decreased desire and fatigue, it thereby affects conception. Hormonal differences between women with MS compared to women without MS include an increase in follicle-stimulating hormone and luteinizing hormone, and a decrease in testosterone. While fluctuations in estrogen result in a reduction in MS relapse rates during pregnancy, a subsequent increase in the post-partum period is observed. The mechanism of action and side effects of DMTs are described in this paper, including interferon, glatiramer acetate, and some newer medications. Although there are no recommended guidelines on the use of DMTs during pregnancy, it is generally agreed upon to cease their use prior to conception if possible, and the decision to continue a DMT should take into account the benefits to the mother and the risks to the fetus. Comprehending the mechanisms of action and teratogenicity indices of DMTs is crucial in understanding their effects on MS during pregnancy, which is an important aspect of providing health care to women with this condition. RésuméLa sclérose en plaques (SP) est l’affection inflammatoire du système nerveux central la plus commune. Le traitement modificateur de la maladie (DMT, de l’anglais) vise à réduire les taux de poussées et à diminuer le nombre de lésions au cerveau et à la moelle épinière. Comme la SP est plus prévalente chez les femmes que chez les hommes, il est important de reconnaître l’interaction entre la SP et la grossesse. Puisque la SP peut engendrer une dysfonction sexuelle, principalement en raison d’une diminution du désir sexuel et de la fatigue, elle affecte la conception. Les différences hormonales entre les femmes avec la SP et les femmes sans la SP incluent une hausse de l’hormone folliculostimulante et de l’hormone lutéinisante, et une baisse de testostérone. Bien que les fluctuations en œstrogènes entraînent en une réduction des taux de poussées de la SP durant la grossesse, leur augmentation subséquente lors de la période postpartum est observée. Le mécanisme d’action et les effets secondaires des DMTs sont décrits dans cet article, incluant l’interféron, l’acétate de glatiramère, et certains autres nouveaux médicaments. Quoiqu’il n’existe pas de lignes directrices sur l’utilisation des DMTs lors de la grossesse, il est généralement accepté qu’il faut cesser leur utilisation avant la conception si possible, et que la décision de continuer la prise d’un DMT devrait tenir compte des avantages pour la mère et des risques pour le fœtus. La compréhension des mécanismes d’action et des effets tératogènes des DMTs est essentielle pour apprécier leurs effets sur la SP durant la grossesse, ce qui constitue un aspect important dans la prestation des soins de santé aux femmes vivant avec cette maladie.
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You, Yuyi, Michael H. Barnett, Con Yiannikas, John D. E. Parratt, Jim G. Matthews, Stuart L. Graham, and Alexander Klistorner. "Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS." Neurology - Neuroimmunology Neuroinflammation 8, no. 3 (February 17, 2021): e971. http://dx.doi.org/10.1212/nxi.0000000000000971.
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ObjectiveTo investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.MethodsOne hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration.ResultsThe annual rates of RNFL and GCIPL thinning were higher in patients treated with “platform” therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = −0.22 μm/y, p = 0.02 for pRNFL; difference = −0.34 μm/y, p = 0.009 for tRNFL; and difference = −0.16 μm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab.ConclusionsProgressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS.Classification of EvidenceThis study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.
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Thakolwiboon, Smathorn, Hannah Zhao-Fleming, Jie Pan, Jordan Knecht Scott, Eri Shoji, Gyeongmo Sohn, and Mirla Avila. "Disease-Modifying Therapies During the COVID-19 Outbreak." International Journal of MS Care 22, no. 4 (May 18, 2020): 151–57. http://dx.doi.org/10.7224/1537-2073.2020-037.
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Abstract Background: Managing multiple sclerosis (MS) during the novel coronavirus disease 2019 (COVID-19) pandemic is a challenge due to the lack of evidence from clinical studies. Disease-modifying therapies (DMTs) may affect the immune response and subsequently alter the risk of COVID-19 infections. Methods: A literature search was conducted on the MEDLINE, Embase, and Cochrane databases. A focused Google search was also performed. Recommendations regarding the use of DMTs during the COVID-19 outbreak from national and international MS/neurology societies were identified and reviewed. Results: The review included 16 recommendations from international and national MS organizations. All recommendations are based on expert opinions. The recommendations regarding DMT initiation and management during this outbreak are summarized. Moreover, the experts’ views about the risk of COVID-19 infection with each DMT are discussed. Conclusions: There is significant agreement among most experts’ recommendations from a variety of sources based on collective clinical experience. However, the recommendations will likely evolve because sufficient clinical data are limited. Several ongoing registries will help provide information for future recommendations.
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Chen, Jing, Bruce V. Taylor, Leigh Blizzard, Steve Simpson Jr, Andrew J. Palmer, and Ingrid A. F. van der Mei. "Effects of multiple sclerosis disease-modifying therapies on employment measures using patient-reported data." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 11 (June 19, 2018): 1200–1207. http://dx.doi.org/10.1136/jnnp-2018-318228.
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BackgroundThe direct comparative evidence on treatment effects of available multiple sclerosis (MS) disease-modifying therapies (DMTs) is limited, and few studies have examined the benefits of DMTs on employment outcomes. We compared the effects of DMTs used in the previous 5 years on improving the work attendance, amount of work and work productivity of people with MS.MethodsThe Australian MS Longitudinal Study collected data from participants on DMTs usage from 2010 to 2015 and whether DMTs contributed to changes in employment outcomes. We classified 11 DMTs into three categories based on their clinical efficacy (β-interferons and glatiramer acetate as category 1; teriflunomide and dimethyl fumarate as category 2; fingolimod, natalizumab, alemtuzumab and mitoxantrone as category 3). Each DMT used by a participant was treated as one observation and analysed by log-multinomial regression.ResultsOf the 874 participants included, 1384 observations were generated. Those who used category 3 (higher efficacy) DMTs were 2–3 times more likely to report improvements in amount of work, work attendance and work productivity compared with those who used category 1 (classical injectable) DMTs. Natalizumab was associated with superior beneficial effects on patient-reported employment outcomes than fingolimod (RR=1.76, 95% CI 1.02 to 3.03 for increased work attendance and RR=1.46, 95% CI 1.02 to 2.10 for increased work productivity).ConclusionsThose using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS.
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Fox, Edward J., Guy J. Buckle, Barry Singer, Vibhuti Singh, and Aaron Boster. "Lymphopenia and DMTs for relapsing forms of MS." Neurology: Clinical Practice 9, no. 1 (January 8, 2019): 53–63. http://dx.doi.org/10.1212/cpj.0000000000000567.
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Purpose of reviewTo provide neurologists with an update on the proposed mechanisms of action (MOAs) of disease-modifying therapies (DMTs) for the treatment of relapsing MS, and their effect on peripheral blood leukocytes, in order to inform treatment decisions.Recent findingsDMTs have vastly differing MOAs, including effects on peripheral blood leukocyte counts, particularly lymphocytes. The clinical implications of changes in lymphocyte counts need to be understood in the context of the underlying MOAs of each respective DMT, with treatment tailored to individual patient needs.SummaryDMTs can alter lymphocyte counts, subsets, activation, and distribution, and thus can influence immune surveillance. Serial monitoring of total leukocytes and absolute lymphocyte counts (ALCs) is advisable in patients receiving DMTs. ALCs should be interpreted regarding expected immunologic changes and individual patient characteristics. Any decision to switch DMTs should consider these factors, along with drug efficacy, safety, and effect on quality of life.
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Cofield, Stacey S., Nina Thomas, Tuula Tyry, Robert J. Fox, and Amber Salter. "Shared Decision Making and Autonomy Among US Participants with Multiple Sclerosis in the NARCOMS Registry." International Journal of MS Care 19, no. 6 (November 1, 2017): 303–12. http://dx.doi.org/10.7224/1537-2073.2016-091.
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Background: Treatment decisions in multiple sclerosis (MS) are affected by many factors and are made by the patient, doctor, or both. With new disease-modifying therapies (DMTs) emerging, the complexity surrounding treatment decisions is increasing, further emphasizing the importance of understanding decision-making preferences. Methods: North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants completed the Fall 2014 Update survey, which included the Control Preferences Scale (CPS). The CPS consists of five images showing different patient/doctor roles in treatment decision making. The images were collapsed to three categories: patient-centered, shared, and physician-centered decision-making preferences. Associations between decision-making preferences and demographic and clinical factors were evaluated using multivariable logistic regression. Results: Of 7009 participants, 79.3% were women and 93.5% were white (mean [SD] age, 57.6 [10.3] years); 56.7% reported a history of relapses. Patient-centered decision making was most commonly preferred by participants (47.9%), followed by shared decision making (SDM; 42.8%). SDM preference was higher for women and those taking DMTs and increased with age and disease duration (all P < .05). Patient-centered decisions were most common for respondents not taking a DMT at the time of the survey and were preferred by those who had no DMT history compared with those who had previously taken a DMT (P < .0001). There was no difference in SDM preference by current MS disease course after adjusting for other disease-related factors. Conclusions: Responders reported most commonly considering their doctor's opinion before making a treatment decision and making decisions jointly with their doctor. DMT use, gender, and age were associated with decision-making preference.
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Thach, Andrew V., Carolyn M. Brown, Vivian Herrera, Rahul Sasane, Jamie C. Barner, Kentya C. Ford, and Kenneth A. Lawson. "Associations Between Treatment Satisfaction, Medication Beliefs, and Adherence to Disease-Modifying Therapies in Patients with Multiple Sclerosis." International Journal of MS Care 20, no. 6 (November 1, 2018): 251–59. http://dx.doi.org/10.7224/1537-2073.2017-031.
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Abstract Background: Adherence to disease-modifying therapy (DMT) remains problematic for many patients with multiple sclerosis (MS). An improved understanding of factors affecting DMT adherence may inform effective interventions. This study examined associations between treatment satisfaction, medication beliefs, and DMT adherence. Methods: A survey was mailed in 2016 to 600 adult patients with relapsing-remitting MS taking an injectable or oral DMT. Patients were sampled from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. The survey measured self-reported DMT adherence (doses taken divided by doses prescribed during previous 2-week period—adherence ≥0.80), DMT satisfaction using the Treatment Satisfaction Questionnaire for Medication version II, medication beliefs using the Beliefs About Medicines Questionnaire, and demographic and clinical covariates. Relationships between variables were examined using multivariate logistic regression. Results: Final analyses included 489 usable surveys. Mean ± SD participant age was 60.5 ± 8.3 years. Most respondents were white (93.8%), female (86.6%), taking an injectable DMT (66.9%), and adherent to DMT (92.8%). Significant predictors of DMT adherence were age (odds ratio [OR], 1.086; 95% CI, 1.020–1.158; P = .011), type of DMT (oral vs. injectable; OR, 23.350; 95% CI, 2.254–241.892; P = .008), and DMT experience (naive vs. experienced; OR, 2.831; 95% CI, 1.018–7.878; P = .046). Conclusions: In patients with MS sampled from a patient registry, treatment satisfaction and medication beliefs were not significantly associated with DMT adherence. Based on significant predictors, younger patients, patients taking injectable DMTs, and patients with previous experience with another DMT(s) are at higher risk for nonadherence. Future research is warranted to assess relationships between variables in more diverse MS populations.