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Dynamic treatment regimens

Carlo Lancia, Cristian Spitoni, Jakob Anninga, Jeremy Whelan, Matthew R Sydes, Gordana Jovic, Marta Fiocco
Marginal structural models are causal models designed to adjust for time-dependent confounders in observational studies with dynamically adjusted treatments. They are robust tools to assess causality in complex longitudinal data. In this paper, a marginal structural model is proposed with an innovative dose-delay joint-exposure model for Inverse-Probability-of-Treatment Weighted estimation of the causal effect of alterations to the therapy intensity. The model is motivated by a precise clinical question concerning the possibility of reducing dosages in a regimen...
January 1, 2018: Statistical Methods in Medical Research
Antoni Xavier Torres-Collado, Ali R Jazirehi
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive...
June 14, 2018: Cancers
Michael W Pfaffl, Irmgard Riedmaier-Sprenzel
The misuse of anabolic hormones or illegal drugs is a ubiquitous problem in animal husbandry and also in food safety. The ban on growth promotants in food producing animals in the European Union is well controlled. However, application regimens that are difficult to detect persist, including newly designed anabolic drugs and complex hormone cocktails. Therefore identification of molecular endogenous biomarkers which are based on the physiological response after the illicit treatment has become a focus of detection methods...
May 31, 2018: Asian-Australasian Journal of Animal Sciences
Zahid Hussain, Mahwish Arooj, Arif Malik, Fahad Hussain, Hassan Safdar, Shahzeb Khan, Muhammad Sohail, Manisha Pandey, Hira Choudhury, Hnin Ei Thu
Development and formulation of an efficient and safe therapeutic regimen for cancer theranostics are dynamically challenging. The use of mono-therapeutic cancer regimen is generally restricted to optimal clinical applications, on account of drug resistance and cancer heterogeneity. Combinatorial treatments can employ multi-therapeutics for synergistic anticancer efficacy whilst reducing the potency of individual moieties and diminishing the incidence of associated adverse effects. The combo-delivery of nanotherapeutics can optimize anti-tumor efficacy while reversing the incidence of drug resistance, aiming to homogenize pharmacological profile of drugs, enhance circulatory time, permit targeted drug accumulation, achieve multi-target dynamic approach, optimize target-specific drug binding and ensure sustained drug release at the target site...
June 6, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Ying Liu, Yuanjia Wang, Michael R Kosorok, Yingqi Zhao, Donglin Zeng
Dynamic treatment regimens (DTRs) are sequential treatment decisions tailored by patient's evolving features and intermediate outcomes at each treatment stage. Patient heterogeneity and the complexity and chronicity of many diseases call for learning optimal DTRs that can best tailor treatment according to each individual's time-varying characteristics (eg, intermediate response over time). In this paper, we propose a robust and efficient approach referred to as Augmented Outcome-weighted Learning (AOL) to identify optimal DTRs from sequential multiple assignment randomized trials...
June 5, 2018: Statistics in Medicine
Adrienne E Swanstrom, Robert J Gorelick, Guoxin Wu, Bonnie Howell, Anitha Vijayagopalan, Rebecca Shoemaker, Kelli Oswald, Siddhartha A Datta, Brandon Keele, Gregory Del Prete, Elena Chertova, Julian Bess, Jeffrey Lifson
Although effective at suppressing viral replication, combination antiretroviral treatment (cART) does not represent definitive therapy of HIV infection due to persistence of replication-competent viral reservoirs. The advent of effective cART regimens for simian immunodeficiency virus (SIV) infected nonhuman primates (NHP) has enabled the development of relevant models for studying viral reservoirs and intervention strategies targeting them. Viral reservoir measurements are crucial for such studies, but are problematic...
June 5, 2018: AIDS Research and Human Retroviruses
Mohammadnabi Asmani, Sanjana Velumani, Yan Li, Nicole Wawrzyniak, Isaac Hsia, Zhaowei Chen, Boris Hinz, Ruogang Zhao
Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure. A major bottleneck in developing new anti-fibrosis therapies is the lack of in vitro models that recapitulate dynamic changes in tissue mechanics during fibrogenesis. Here we create membranous human lung microtissues to model key biomechanical events occurred during lung fibrogenesis including progressive stiffening and contraction of alveolar tissue, decline in alveolar tissue compliance and traction force-induced bronchial dilation...
May 25, 2018: Nature Communications
Bashir Kaka, Omoyemi O Ogwumike, Ade F Adeniyi, Sonill S Maharaj, Samuel O Ogunlade, Bashir Bello
BACKGROUND AND AIMS: Non-specific neck pain (NsNP) constitutes a burden to the bearers and a management challenge to physiotherapists globally. Effectiveness of neck stabilisation and dynamic exercises in the management of NsNP has been documented, but it is not clear which exercise regimen is more effective in alleviating its associated pain, depression and anxiety. This study was carried out to compare the effectiveness of neck stabilisation and/or dynamic exercises on pain intensity, depression and anxiety among patients with NsNP...
April 25, 2018: Scandinavian Journal of Pain
Sidra Rehman, Usman Ali Ashfaq, Bushra Ijaz, Sheikh Riazuddin
BACKGROUND: Without an effective vaccine, hepatitis C virus (HCV) remains a global threat, inflicting 170-300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma (HCC). Though various direct acting antivirals have been redeemed the hepatitis C treatment, a few restraints persist including possible side effects, viral resistance emergence, excessive cost which restricts its availability to a common person. HYPOTHESIS: There is no preventive HCV vaccine available today so the discovery of potent antiviral natural flora and their bioactive constituents may help to develop preventive cures against HCV infection...
May 15, 2018: Microbial Pathogenesis
Anusha Ande, Tanaya R Vaidya, Bao N Tran, Michael Vicchiarelli, Ashley N Brown, Sihem Ait-Oudhia
Background: Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance. Methods: Static (two dimensional, 2D) and three-dimensional dynamic (3DD) cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies...
2018: Frontiers in Pharmacology
Nicolas A Menzies, Ted Cohen, Andrew N Hill, Reza Yaesoubi, Kara Galer, Emory Wolf, Suzanne M Marks, Joshua A Salomon
We estimated long-term tuberculosis (TB) trends in the US population and assessed prospects for TB elimination. We used a detailed simulation model allowing for changes in TB transmission, immigration, and other TB risk determinants. We evaluated 5 hypothetical scenarios from 2017 to 2100: 1) maintain current TB prevention and treatment activities (base-case), 2) provision of latent TB infection testing and treatment for new legal immigrants, 3) increased uptake of latent TB infection screening and treatment among high-risk populations, including a 3-month isoniazid-rifapentine regimen, 4) improved TB case detection, 5) improved TB treatment quality...
May 14, 2018: American Journal of Epidemiology
Sharea Ijaz, Philippa Davies, Catherine J Williams, David Kessler, Glyn Lewis, Nicola Wiles
BACKGROUND: Antidepressants are a first-line treatment for adults with moderate to severe major depression. However, many people prescribed antidepressants for depression don't respond fully to such medication, and little evidence is available to inform the most appropriate 'next step' treatment for such patients, who may be referred to as having treatment-resistant depression (TRD). National Institute for Health and Care Excellence (NICE) guidance suggests that the 'next step' for those who do not respond to antidepressants may include a change in the dose or type of antidepressant medication, the addition of another medication, or the start of psychotherapy...
May 14, 2018: Cochrane Database of Systematic Reviews
Elsje Pienaar, Jennifer J Linderman, Denise E Kirschner
Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas...
2018: PloS One
Laurence A Hutton-Smith, Eamonn A Gaffney, Helen M Byrne, Antonello Caruso, Philip K Maini, Norman Alan Mazer
Neovascular age-related macular degeneration (wet AMD) results from the pathological angiogenesis of choroidal capillaries, which leak fluid within or below the macular region of the retina. The current standard of care for treating wet AMD utilizes intravitreal injections of anti-VEGF antibodies or antibody fragments to suppress ocular VEGF levels. While VEGF suppression has been demonstrated in wet AMD patients by serial measurements of free-VEGF concentrations in aqueous humor samples, it is presumed that anti-VEGF molecules also permeate across the inner limiting membrane (ILM) of the retina as well as the retinal pigmented epithelium (RPE) and suppress VEGF-levels in the retina and/or choroidal regions...
May 7, 2018: Molecular Pharmaceutics
Lisanne Lutter, Julia Spierings, Femke C C van Rhijn-Brouwer, Jacob M van Laar, Femke van Wijk
Autologous hematopoietic stem cell transplantation (aHSCT) for autoimmune diseases has been applied for two decades as a treatment for refractory patients with progressive disease. The rationale behind aHSCT is that high-dose immunosuppression eliminates autoreactive T and B cells, thereby resetting the immune system. Post-aHSCT the cytotoxic CD8+ T cells normalize via clonal expansion due to homeostatic proliferation within a few months. CD4+ T cells recover primarily via thymopoiesis resulting in complete renewal of the T cell receptor (TCR) repertoire which requires years or never normalize completely...
2018: Frontiers in Immunology
Nenad Macesic, Angela Gomez-Simmonds, Sean B Sullivan, Marla J Giddins, Samantha A Ferguson, Gautam Korakavi, David Leeds, Sarah Park, Kevin Shim, Madeleine G Sowash, Melanie Hofbauer, Ryan Finkel, Yue Hu, Jared West, Nora C Toussaint, William G Greendyke, Benjamin A Miko, Marcus R Pereira, Susan Whittier, Elizabeth C Verna, Anne-Catrin Uhlemann
Background: Multidrug-resistant organisms (MDROs) are an important cause of morbidity and mortality after solid organ transplantation. We aimed to characterize MDRO colonization dynamics and infection in liver transplant (LT) recipients through innovative use of active surveillance and whole-genome sequencing (WGS). Methods: We prospectively enrolled consecutive adult patients undergoing LT from March 2014 to March 2016. Fecal samples were collected at multiple timepoints from time of enrollment to 12 months posttransplant...
April 28, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Xiao-Xue Zhu, Da-Long Zhu, Xiao-Ying Li, Ya-Lin Li, Xiao-Wei Jin, Tian-Xin Hu, Yu Zhao, Yong-Guo Li, Gui-Yu Zhao, Shuang Ren, Yi Zhang, Yan-Hua Ding, Li Chen
AIMS: To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic β-cell function in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed...
April 29, 2018: Diabetes, Obesity & Metabolism
Abu Naser Mohon, Didier Menard, Mohammad Shafiul Alam, Kevin Perera, Dylan R Pillai
Background: Artemisinin-resistant malaria (ARM) remains a significant threat to malaria elimination. In the Greater Mekong subregion, the prevalence of ARM in certain regions has reached greater than 90%. Artemisinin-resistant malaria is clinically identified by delayed parasite clearance and has been associated with mutations in the propeller domain of the kelch 13 gene. C580Y is the most prevalent mutation. The detection of ARM currently relies on labor-intensive and time-consuming methods such as clinical phenotyping or in vitro susceptibility testing...
April 2018: Open Forum Infectious Diseases
Iu M Stoĭko, O B Talibov, M N Iashkin, M N Kudykin, S M Belentsov, O V Katel'nitskaia, I A Suchkov, V Iu Tolstikhin, A É Kletskin, K S Sevost'ianova
The purpose of the study was to evaluate efficacy of Diosmin (Phlebodia 600, Innothera, France) in treatment of patients presenting with class C0s-C3 chronic venous diseases (CVD) according to the CEAP classification. Presented herein are the results of a prospective observational study aimed at assessing the outcomes of two-month administration of Phlebodia 600 (600 mg diosmin) in patients suffering from class C0s-C3 CVD according to the CEAP classification. The study comprised a total of 868 patients, including 175 (20...
2018: Angiologii︠a︡ i Sosudistai︠a︡ Khirurgii︠a︡, Angiology and Vascular Surgery
Begum Aydogan Mathyk, Berna Aslan Cetin, Duygu Vardagli, Emel Zengin, Nigar Sofiyeva, Tulay Irez, Pelin Ocal
OBJECTIVE: A high dose of prolonged gonadotropins can yield higher numbers of oocytes and embryos. The high dose or prolonged regimens can be associated with ovarian hyperstimulation syndrome (OHSS), multiple gestations, emotional stress, economical burden and treatment dropout. In mild stimulation lower doses and shorter duration times of gonadotropin are used in contrast to the conventional long stimulation protocol in IVF. It has been proposed that supraphysiologic levels of hormones may adversely affect endometrium and oocyte/embryo...
April 2018: Taiwanese Journal of Obstetrics & Gynecology
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