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Physical Review. E Nov 2018Estimation of mutual information between random variables has become crucial in a range of fields, from physics to neuroscience to finance. Estimating information...
Estimation of mutual information between random variables has become crucial in a range of fields, from physics to neuroscience to finance. Estimating information accurately over a wide range of conditions relies on the development of flexible methods to describe statistical dependencies among variables, without imposing potentially invalid assumptions on the data. Such methods are needed in cases that lack prior knowledge of their statistical properties and that have limited sample numbers. Here we propose a powerful and generally applicable information estimator based on non-parametric copulas. This estimator, called the non-parametric copula-based estimator (NPC), is tailored to take into account detailed stochastic relationships in the data independently of the data's marginal distributions. The NPC estimator can be used both for continuous and discrete numerical variables and thus provides a single framework for the mutual information estimation of both continuous and discrete data. By extensive validation on artificial samples drawn from various statistical distributions, we found that the NPC estimator compares well against commonly used alternatives. Unlike methods not based on copulas, it allows an estimation of information that is robust to changes of the details of the marginal distributions. Unlike parametric copula methods, it remains accurate regardless of the precise form of the interactions between the variables. In addition, the NPC estimator had accurate information estimates even at low sample numbers, in comparison to alternative estimators. The NPC estimator therefore provides a good balance between general applicability to arbitrarily shaped statistical dependencies in the data and shows accurate and robust performance when working with small sample sizes. We anticipate that the non-parametric copula information estimator will be a powerful tool in estimating mutual information between a broad range of data.
PubMed: 30984901
DOI: 10.1103/PhysRevE.98.053302 -
Thrombosis Research Oct 2020Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous... (Review)
Review
BACKGROUND
Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented.
OBJECTIVE
This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice.
METHODS
A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included.
RESULTS
A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction.
CONCLUSION
Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events.
Topics: Administration, Oral; Anticoagulants; Drug Interactions; Hemorrhage; Humans; Observational Studies as Topic; Pharmaceutical Preparations; Retrospective Studies
PubMed: 33213849
DOI: 10.1016/j.thromres.2020.08.016 -
Acta Veterinaria Scandinavica Dec 2021Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP,... (Review)
Review
Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP, but treatment failure may occur. Immunomodulatory and non-corticosteroid immunosuppressive drugs might improve outcomes from therapy either alone or in combination with corticosteroids. The objectives of this scoping review were (1) to evaluate the current evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP, and (2) to answer the clinical question, whether or not therapy with immunomodulatory or non-corticosteroid immunosuppressive drugs alone or in combination with corticosteroids could improve outcome, compared to therapy with corticosteroids alone. A literature search was performed in the electronic databases of Agricola, CAB Abstracts, Embase, Medline and Web of Science for publications in November 2019 and again February 1, 2021. Selection criteria were relatively strict and included peer-reviewed research papers reporting outcome measures from immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP with a pre-therapeutic mean or median platelet count < 50,000/µL as a strict criterion for inclusion. Studies were evaluated if they had an appropriate diagnostic work up to exclude underlying conditions. Outcome measures and adverse events were compared between drug protocols both within studies and between studies. The search identified 456 studies, with six studies being eligible for inclusion. The studies were mostly case series while two were randomized controlled trials. Level of evidence varied with an overall uncertain subject enrollment, small groups, inadequate description and variable use of drug protocols or outcome measures. For outcomes such as platelet recovery time and duration of hospitalization, an improvement was observed using adjunctive therapy (human intravenous immunoglobulin) compared to therapy with corticosteroids alone. For outcomes of complete platelet recovery time, survival (6-month), mortality and relapse, no improvement was observed using adjunctive drugs compared to corticosteroids alone. Specifically, therapy with mycophenolate mofetil alone and adjunctive azathioprine were associated with more severe adverse events compared to other drug protocols. Evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP was of variable quality. Future larger case-controlled trials are required for determination of optimal treatment protocols in canine ITP.
Topics: Animals; Blood Platelets; Dog Diseases; Dogs; Immunosuppressive Agents; Pharmaceutical Preparations; Platelet Count; Purpura, Thrombocytopenic, Idiopathic
PubMed: 34961516
DOI: 10.1186/s13028-021-00620-z -
European Journal of Pharmaceutical... Sep 2022Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a... (Review)
Review
Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a first-in-class medicinal product recommended in the treatment of metastatic castration resistant prostate cancer (mCRPC) that targets androgen receptors and inhibits systemic synthesis. However, successful therapy with this drug may pose some challenges. It has to be administered as an inactive prodrug - abiraterone acetate. It is also dissolved and absorbed poorly with large interindividual variability and exhibits considerable food effects. Additionally, the recommended daily dose of the drug is high (1000 mg abiraterone acetate), and the cost of the therapy is burdensome. The following review focuses on the strategies to optimize therapy with abiraterone acetate. First, it summarizes current findings on abiraterone pharmacokinetics and accentuates the need for utilizing therapeutic monitoring in clinical practice. Next, it extensively describes the options for improving the low bioavailability of the drug. The two major approaches are the utilization of the positive food effect to increase the exposure and development of supergenerics. The review emphasizes how different formulation approaches lead to increased solubility and impact the outcomes of pre-clinical and clinical trials. The review concludes with a discussion on possible future directions that may lead to the increase of the therapeutic efficacy of abiraterone.
Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Drug Monitoring; Humans; Male; Pharmaceutical Preparations; Prostatic Neoplasms, Castration-Resistant
PubMed: 35793751
DOI: 10.1016/j.ejps.2022.106254 -
American Journal of Pharmaceutical... Dec 2019To evaluate change in the ability of third-year pharmacy students to identify drugs that increase fall risk after training in and experience using the Medication Falls...
To evaluate change in the ability of third-year pharmacy students to identify drugs that increase fall risk after training in and experience using the Medication Falls Risk Assessment Tool (MFRAT). An assessment was administered to students prior to MFRAT use and after MFRAT use. The assessment consisted of 10 medication regimens for various chronic conditions (50 distinct drug choices with 30 correct answers and 20 distractors), and students were to identify fall risk increasing drugs (FRIDs). Using a flipped-classroom approach, students viewed an online presentation on FRIDs and then participated in instructor guided, in-class application of the MFRAT using student-collected data from an actual patient case. Students completed medication therapy management (MTM) documentation. The assessment data for students who had previously used the MFRAT (experienced) were analyzed separately from first time users (inexperienced). Three assessment scores were evaluated: number correct (maximum 30; higher score is better), number of distractors (maximum 20; lower score better), and a combined total score (maximum 50; higher score better). In inexperienced users (n=104), pre- and post-assessment means improved significantly for correct score (24.9 vs 29.5) and total score (39.4 vs 44.3). Among experienced users (n=10), pre- and post-assessment means improved significantly for correct responses (27.3 vs 29.7), distractors (7.0 vs 3.5), and total score (40.3 vs 46.2). The ability of both pharmacy students who had used the MFRAT previously and those who had not to correctly identify FRIDs increased on the post-assessment.
Topics: Accidental Falls; Curriculum; Drug-Related Side Effects and Adverse Reactions; Education, Pharmacy; Educational Measurement; Humans; Medication Therapy Management; Pharmaceutical Preparations; Risk; Risk Assessment; Students, Pharmacy
PubMed: 32001880
DOI: 10.5688/ajpe7461 -
Clinical and Translational Science Mar 2023The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top... (Review)
Review
The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top priority. The use of imaging biomarkers has been associated with increased rates of drug approvals. An appropriate level of validation provides a pragmatic way to choose and implement these biomarkers. Standardizing imaging modality selection, data acquisition protocols, and image analysis (in ways that are agnostic to equipment and algorithms) have been key to imaging biomarker deployment. The best known examples come from studies done via precompetitive collaboration efforts, which enable input from multiple stakeholders and data sharing. Digital health technologies (DHTs) provide an opportunity to measure meaningful aspects of patient health, including patient function, for extended periods of time outside of the hospital walls, with objective, sensor-based measures. We identified the areas where learnings from the imaging biomarker field can accelerate the adoption and widespread use of DHTs to develop novel treatments. As with imaging, technical validation parameters and performance acceptance thresholds need to be established. Approaches amenable to multiple hardware options and data processing algorithms can be enabled by sharing DHT data and by cross-validating algorithms. Data standardization and creation of shared databases will be vital. Pre-competitive consortia (public-private partnerships and professional societies that bring together all stakeholders, including patient organizations, industry, academic experts, and regulators) will advance the regulatory maturity of DHTs in clinical trials.
Topics: Humans; Pharmaceutical Preparations; Information Dissemination; Power, Psychological
PubMed: 36382716
DOI: 10.1111/cts.13461 -
PLoS Neglected Tropical Diseases Feb 2018Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare... (Review)
Review
BACKGROUND
Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns.
METHODOLOGY/ PRINCIPAL FINDINGS
We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%).
CONCLUSIONS/SIGNIFICANCE
Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs.
Topics: Community Health Services; Databases, Factual; Delivery of Health Care; Health Education; Health Promotion; Humans; Immunization Programs; Meta-Analysis as Topic; Motivation; Pharmaceutical Preparations; Public Health; Public Health Administration; School Health Services; Vaccines
PubMed: 29420534
DOI: 10.1371/journal.pntd.0006211 -
Drug Discovery Today. Technologies Dec 2021Data-independent acquisition (DIA) proteomics is a recently-developed global mass spectrometry (MS)-based proteomics strategy. In a DIA method, precursor ions are... (Review)
Review
Data-independent acquisition (DIA) proteomics is a recently-developed global mass spectrometry (MS)-based proteomics strategy. In a DIA method, precursor ions are isolated into pre-defined isolation windows and fragmented; all fragmented ions in each window are then analyzed by a high-resolution mass spectrometer. DIA proteomics analysis is characterized by a broad protein coverage, high reproducibility, and accuracy, and its combination with advances in other techniques such as sample preparation and computational data analysis could lead to further improvements in assay performances. DIA technology has been increasingly utilized in various proteomics studies, including quantifying drug-metabolizing enzymes and transporters. Quantitative proteomics study of drug-metabolizing enzymes and transporters could lead to a better understanding of pharmacokinetics and pharmacodynamics and facilitate drug development. This review summarizes the application of DIA technology in proteomic analysis of drug-metabolizing enzymes and transporters.
Topics: Mass Spectrometry; Pharmaceutical Preparations; Proteomics; Reproducibility of Results; Technology
PubMed: 34906325
DOI: 10.1016/j.ddtec.2021.06.006 -
Physical Review. E Mar 2020Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each...
Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each other, indicating that cooperative binding of cofilin is mediated by the actin filament lattice. Cofilactin is therefore a model system for studying allosteric regulation of self-assembly. How cofilin binding changes structural and mechanical properties of actin filaments is well established. Less is known about the interaction energies and the thermodynamics of filament fragmentation, which describes the collective manner in which the cofilin concentration controls mean actin filament length. Here, we provide a general thermodynamic framework for allosteric regulation of self-assembly, and we use the theory to predict the interaction energies of experimental actin filament length distributions over a broad range of cofilin binding densities and for multiple cofilactin variants. We find that bound cofilin induces changes in nearby actin-actin interactions, and that these allosteric effects are propagated along the filament to affect up to four neighboring cofilin-binding sites (i.e., beyond nearest-neighbor allostery). The model also predicts that cofilin differentially stabilizes and destabilizes longitudinal versus lateral actin-actin interactions, and that the magnitude, range, asymmetry, and even the sign of these interaction energies can be altered using different actin and cofilin mutational variants. These results demonstrate that the theoretical framework presented here can provide quantitative thermodynamic information governing cooperative protein binding and filament length regulation, thus revealing nanometer length-scale interactions from micron length-scale "wet-lab" measurements.
Topics: Allosteric Regulation; Cytoskeletal Proteins; Models, Molecular; Thermodynamics
PubMed: 32290018
DOI: 10.1103/PhysRevE.101.032409 -
BMC Public Health May 2021Recreational and sexual drug use among men who have sex with men may result in increased risk of poor health. The aim of this study was to better understand drug use and...
Sex, drugs and techno - a qualitative study on finding the balance between risk, safety and pleasure among men who have sex with men engaging in recreational and sexualised drug use.
BACKGROUND
Recreational and sexual drug use among men who have sex with men may result in increased risk of poor health. The aim of this study was to better understand drug use and harm reduction techniques among Swedish men who have sex with men traveling to Berlin in order to improve the health of this population and inform public health strategies.
METHODS
A qualitative study based on semi-structured interviews with 15 Swedish men aged 23-44 with experience of drug use were recruited through network sampling. Interviews were conducted in Stockholm and Berlin and analysed using content analysis. The interview guide included questions on drug use, context, health and safety.
RESULTS
The participants engaged in drug use in both settings and in various contexts. Participants saw themselves as capable of finding a balance between pleasure, safety and risk with the aim to maximize positive effects while minimizing negative ones. The different risks of drug use were known, and participants relied on knowledge, harm reduction strategies and self-defined rules of intake to stay safe and healthy in a broad sense, both short term (i.e. during each session) and long term. Choice of drug and, frequency of intake, multi-use, risk of overdose, risk of HIV, purpose and context of use, how often, etc. were all part of the overall strategy. Knowledge of these methods was spread within the community and on-line rather than from counsellors or other health care providers. However, it did not always translate perfectly into practice and some had experienced overdoses and problematic use.
CONCLUSIONS
The findings of this study point to the need for increased adoption of harm reduction techniques in this population focusing on mitigating harm and prevention of risk of problematic use or starting injection drugs. Existing traditional services require adaptations to become more accessible and acceptable to sub-groups of drug users, including low-threshold services providing non-judgemental, evidence-based information. This will require funding of alternative providers such as STI/HIV clinics, among others, and health care providers to increase adoption of prevention strategies, specifically pre-exposure prophylaxis for HIV.
Topics: Adult; Berlin; HIV Infections; Homosexuality, Male; Humans; Male; Pharmaceutical Preparations; Pleasure; Sexual Behavior; Sexual and Gender Minorities; Sweden; Young Adult
PubMed: 33952247
DOI: 10.1186/s12889-021-10906-6