Laboratory Exercises to Teach Clinically Relevant Chemistry of Antibiotics

PubMed Central

Chelette, Candace T.

2014-01-01

Objectives. To design, implement, and evaluate student performance on clinically relevant chemical and spectral laboratory exercises on antibiotics. Design. In the first of 2 exercises, second-year pharmacy students enrolled in an integrated laboratory sequence course studied the aqueous stability of ß-lactam antibiotics using a spectral visual approach. In a second exercise, students studied the tendency of tetracycline, rifamycins, and fluoroquinolones to form insoluble chelate complexes (turbidity) with polyvalent metals. Assessment. On a survey to assess achievement of class learning objectives, students agreed the laboratory activities helped them better retain important information concerning antibiotic stability and interactions. A significant improvement was observed in performance on examination questions related to the laboratory topics for 2012 and 2013 students compared to 2011 students who did not complete the laboratory. A 1-year follow-up examination question administered in a separate course showed >75% of the students were able to identify rifamycins-food interactions compared with <25% of students who had not completed the laboratory exercises. Conclusion. The use of spectral visual approaches allowed students to investigate antibiotic stability and interactions, thus reinforcing the clinical relevance of medicinal chemistry. Students’ performance on questions at the 1-year follow-up suggested increased retention of the concepts learned as a result of completing the exercises. PMID:24672070

Laboratory exercises to teach clinically relevant chemistry of antibiotics.

PubMed

El Sayed, Khalid A; Chelette, Candace T

2014-03-12

To design, implement, and evaluate student performance on clinically relevant chemical and spectral laboratory exercises on antibiotics. In the first of 2 exercises, second-year pharmacy students enrolled in an integrated laboratory sequence course studied the aqueous stability of ß-lactam antibiotics using a spectral visual approach. In a second exercise, students studied the tendency of tetracycline, rifamycins, and fluoroquinolones to form insoluble chelate complexes (turbidity) with polyvalent metals. On a survey to assess achievement of class learning objectives, students agreed the laboratory activities helped them better retain important information concerning antibiotic stability and interactions. A significant improvement was observed in performance on examination questions related to the laboratory topics for 2012 and 2013 students compared to 2011 students who did not complete the laboratory. A 1-year follow-up examination question administered in a separate course showed >75% of the students were able to identify rifamycins-food interactions compared with <25% of students who had not completed the laboratory exercises. The use of spectral visual approaches allowed students to investigate antibiotic stability and interactions, thus reinforcing the clinical relevance of medicinal chemistry. Students' performance on questions at the 1-year follow-up suggested increased retention of the concepts learned as a result of completing the exercises.

On the intersection of phonetic detail and the organization of interaction: clinical connections.

PubMed

Walker, Gareth; Local, John

2013-01-01

The analysis of language use in real-world contexts poses particular methodological challenges. We codify responses to these challenges as a series of methodological imperatives. To demonstrate the relevance of these imperatives to clinical investigation, we present analyses of single episodes of interaction where one participant has a speech and/or language impairment: atypical prosody, echolalia and dysarthria. We demonstrate there is considerable heuristic and analytic value in taking this approach to analysing the organization of interaction involving individuals with a speech and/or language impairment.

Enteral feeding: drug/nutrient interaction.

PubMed

Lourenço, R

2001-04-01

Enteral nutrition support via a feeding tube is the first choice for artificial nutrition. Most patients also require simultaneous drug therapy, with the potential risk for drug-nutrient interactions which may become relevant in clinical practice. During enteral nutrition, drug-nutrient interactions are more likely to occur than in patients fed orally. However, there is a lack of awareness about its clinical significance, which should be recognised and prevented in order to optimise nutritional and pharmacological therapeutic goals of safety and efficacy. To raise the awareness of potential drug-nutrient interactions and influence on clinical outcomes. To identify factors that can promote drug-nutrient interactions and contribute to nutrition and/or therapeutic failure. To be aware of different types of drug-nutrient interactions. To understand complex underlying mechanisms responsible for drug-nutrient interactions. To learn basic rules for the administration of medications during tube-feeding. Copyright 2001 Harcourt Publishers Ltd.

Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: invasion, angiogenesis, metastasis and therapy.

PubMed

Santos, A A; Matos, A J F

2015-08-01

Significant advances have been made recently in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly the interactions of neoplastic cells with stromal and immune cells, is crucial for the development of novel effective therapeutic agents and strategies. This second part of a two-part review discusses some of the latest advances in the understanding of the clinically relevant genetic and molecular pathways involved in metastasis and in the interactions between tumour and stromal cells, including inflammatory and immune cells, cancer-associated fibroblasts, and endothelial cells. Recent experimental data on the role of matrix-degrading proteases and angiogenic factors are also discussed. Finally, the clinical utility of different non-surgical therapeutic modalities is reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Individual variability in clinical effect and tolerability of opioid analgesics - Importance of drug interactions and pharmacogenetics.

PubMed

Solhaug, Vigdis; Molden, Espen

2017-10-01

As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount ('dose') of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Drug interactions and pharmacogenetic differences may lead to therapeutic failure or serious side effects of opioid analgesics. Many interactions involve combinations with antidepressants and antiepileptics, which are highly relevant drugs in patients suffering from pain. To prevent unfavourable drug interactions it is important that clinicians pay close attention and use electronic drug interaction checkers when treatments are initiated or discontinued. For the management of issues related to pharmacogenetic differences, blood-based CYP genotyping is available as routine test at many laboratories, and provide a valuable tool for proper choice of drugs and doses for treatment of pain and other diseases. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Interpersonal behaviors and socioemotional interaction of medical students in a virtual clinical encounter

PubMed Central

2014-01-01

Background The virtual clinical encounter (VCE) may function as an important support for medical students in or prior to clinical practice to train and ease communication and socioemotional interactions with patients. Few studies have however focused on the dynamics of interpersonal behaviors in clinical interviewing with a virtual patient (VP) and the affective responses evoked by such a learning experience. The study was designed to investigate the dynamics and congruence of interpersonal behaviors and socioemotional interaction exhibited during the learning experience in a VCE, and to evaluate which interaction design characteristics contribute most to the behavioral and affective engagement in medical students. Methods Thirty medical students (sixth semester) participated voluntarily in an exploratory observational study with a highly interactive VP case based on a trustworthy VP encounter with a natural and realistic dialogue interface. Students worked collaboratively in pairs. They were videotaped for further behavioral analysis and self-reported (in both a survey and an interview) their personal opinions, perceptions and attitudes about the VCE. A mixed methods approach was applied. Results All participants demonstrated an adequate, respectful and relevant clinical case management and to obtain psychosocial history. The collaborative workspace played its role and led to dynamic and engaged discussions fostering thus shared understanding. The results suggest that the VCE studied was perceived as a meaningful, intrinsically motivational and activating learning environment, and was found to socially and emotionally engage learners. We also found that VCEs have the potential to support the development of relevant and congruent interpersonal communication skills in trainees. Conclusions By taking advantage of socioemotional interaction, VCEs promote not only critical reflection skills or strategy-selection skills, but also to develop listening and nonverbal skills, induce self-awareness and target coping behaviours. We believe that, if applied in early medical education, this learning approach may facilitate clinical encounters at an early stage and contribute to responsible clinical decision making. PMID:24685070

Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients.

PubMed

Zorina, Olesya I; Haueis, Patrick; Semmler, Alexander; Marti, Isabelle; Gonzenbach, Roman R; Guzek, Markus; Kullak-Ublick, Gerd A; Weller, Michael; Russmann, Stefan

2012-08-01

The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs. Copyright © 2012 John Wiley & Sons, Ltd.

The Acceptability and Representativeness of Standardized Parent-Child Interaction Tasks

ERIC Educational Resources Information Center

Rhule, Dana M.; McMahon, Robert J.; Vando, Jessica

2009-01-01

Analogue behavioral observation of structured parent-child interactions has often been used to obtain a standardized, unbiased measure of child noncompliance and parenting behavior. However, for assessment information to be clinically relevant, it is essential that the behavior observed be similar to that which the child normally experiences and…

Prevalence and typology of potential drug interactions occurring in primary care patients.

PubMed

Lopez-Picazo, Julio J; Ruiz, Juan C; Sanchez, Jose F; Ariza, Angeles; Aguilera, Belen; Lazaro, Dolores; Sanz, Gonzalo R

2010-06-01

To investigate the prevalence and types of potential drug interactions in primary care patients to detect risky prescriptions as an essential condition to design intervention policies leading to an improvement in patient safety. Cross-sectional descriptive study. Two areas in Spain comprising 715,661 inhabitants. 430,525 subjects with electronic medical records and assigned to a family doctor regularly updating them. On a random day, 29.4% of the population was taking medication. Of these, 73.9% were at risk of suffering interactions, and these were found in 20.6% of them. The amount of interactions was higher among people with chronic conditions, the elderly, females and polymedicated patients. From the total of interactions, 55.1% belonged to the highest clinical relevance 'A' level, and 28.3% should have been avoided. The active ingredients primarily involved were hydrochlorothiazide and ibuprofen and, when focusing on those that should be avoided, omeprazole and acenocoumarol. The most frequent 'A' interaction that should be avoided was between non-conjugated excreted benzodiazepines and proton-pump inhibitors, followed by some NSAIDs and diuretics. 1 in 20 Spanish citizens is currently undergoing a potential drug interaction, including a high rate of clinically relevant ones that should be avoided. These results confirm the existence of a serious safety issue that should be approached and where all parties involved (physicians, health services, medical societies and patients) must do our bit to improve. Health services should foster the implementation of prescription alert systems linked with electronic medical records including clinical data.

Towards clinically translatable in vivo nanodiagnostics

NASA Astrophysics Data System (ADS)

Park, Seung-Min; Aalipour, Amin; Vermesh, Ophir; Yu, Jung Ho; Gambhir, Sanjiv S.

2017-05-01

Nanodiagnostics as a field makes use of fundamental advances in nanobiotechnology to diagnose, characterize and manage disease at the molecular scale. As these strategies move closer to routine clinical use, a proper understanding of different imaging modalities, relevant biological systems and physical properties governing nanoscale interactions is necessary to rationally engineer next-generation bionanomaterials. In this Review, we analyse the background physics of several clinically relevant imaging modalities and their associated sensitivity and specificity, provide an overview of the materials currently used for in vivo nanodiagnostics, and assess the progress made towards clinical translation. This work provides a framework for understanding both the impressive progress made thus far in the nanodiagnostics field as well as presenting challenges that must be overcome to obtain widespread clinical adoption.

Lack of Impact by SCY-078, a First-in-Class Oral Fungicidal Glucan Synthase Inhibitor, on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports the Low Risk for Clinically Relevant Metabolic Drug-Drug Interactions.

PubMed

Wring, Stephen; Murphy, Gail; Atiee, George; Corr, Christy; Hyman, Michele; Willett, Michael; Angulo, David

2018-05-10

SCY-078, the first in a new class of β 1,3-glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY-078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of the potential interaction with SCY-078, this phase 1, open-label, 2-period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY-078 dosed to therapeutically relevant SCY-078 concentration exposure after repeat dosing. Healthy adult subjects were randomized to 2 treatment sequences: a single oral 4-mg rosiglitazone dose alone on day 1 or a 1250-mg SCY-078 loading dose on day 1 followed by a once-daily 750-mg SCY-078 dose for an additional 7 days (reflecting the clinical regimen evaluated during phase 2 studies for infections by Candida species) and concurrent administration of a single oral 4-mg rosiglitazone dose on day 3, before alternating following a ≥10-day washout. The exposure to SCY-078 observed in this study was in line with the intended exposure for treatment of invasive fungal infections. The 90% confidence intervals for rosiglitazone exposure geometric mean ratios were within the prespecified no effect interval of 0.70-1.43. Additionally, maximum concentration values for rosiglitazone and its metabolite, N-desmethylrosiglitazone, were not significantly affected by co-administration with SCY-078. Overall, rosiglitazone exposure was not impacted to a clinically meaningful extent with co-administration of therapeutically relevant SCY-078 concentration exposure after repeat dosing. The results are indicative of low risk for interaction of SCY-078 with drugs metabolized via the CYP family of enzymes. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Multiple Levels of Suffering

PubMed Central

Kiley, Kasey B.; Haywood, Carlton; Bediako, Shawn M.; Lanzkron, Sophie; Carroll, C. Patrick; Buenaver, Luis F.; Pejsa, Megan; Edwards, Robert R.; Haythornthwaite, Jennifer A.; Campbell, Claudia M.

2016-01-01

Objective: People living with sickle cell disease (SCD) experience severe episodic and chronic pain and frequently report poor interpersonal treatment within health-care settings. In this particularly relevant context, we examined the relationship between perceived discrimination and both clinical and laboratory pain. Methods: Seventy-one individuals with SCD provided self-reports of experiences with discrimination in health-care settings and clinical pain severity, and completed a psychophysical pain testing battery in the laboratory. Results: Discrimination in health-care settings was correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, as well as stress, depression, and sleep. After controlling for relevant covariates, discrimination remained a significant predictor of mechanical temporal summation (a marker of central pain facilitation), but not clinical pain severity or suprathreshold heat pain response. Furthermore, a significant interaction between experience with discrimination and clinical pain severity was associated with mechanical temporal summation; increased experience with discrimination was associated with an increased correlation between clinical pain severity and temporal summation of pain. Discussion: Perceived discrimination within health-care settings was associated with pain facilitation. These findings suggest that discrimination may be related to increased central sensitization among SCD patients, and more broadly that health-care social environments may interact with pain pathophysiology. PMID:26889615

[Terbinafine : Relevant drug interactions and their management].

PubMed

Dürrbeck, A; Nenoff, P

2016-09-01

The allylamine terbinafine is the probably most frequently prescribed systemic antifungal agent in Germany for the treatment of dermatomycoses and onychomycoses. According to the German drug law, terbinafine is approved for patients who are 18 years and older; however, this antifungal agent is increasingly used off-label for treatment of onychomycoses and tinea capitis in children. Terbinafine is associated with only a few interactions with other drugs, which is why terbinafine can generally be used without problems in older and multimorbid patients. Nevertheless, some potential interactions of terbinafine with certain drug substances are known, including substances of the group of antidepressants/antipsychotics and some cardiovascular drugs. Decisive for the relevance of interactions is-along with the therapeutic index of the substrate and the possible alternative degradation pathways-the genetically determined type of metabolism. When combining terbinafine with tricyclic antidepressants or selective serotonin reuptake inhibitors and serotonin/noradrenalin reuptake inhibitors, the clinical response and potential side effects must be monitored. Problematic is the use of terbinafine with simultaneous treatment with tamoxifen. The administration of potent CYP2D6 inhibitors leads to a diminished efficacy of tamoxifen because one of its most important active metabolites-endoxifen-is not sufficiently available. Therefore, combination of tamoxifen and terbinafine should be avoided. In conclusion, the number of substances which are able to cause clinically relevant interactions in case of simultaneously administration with terbinafine is clear and should be manageable in the dermatological office with adequate monitoring.

CLINICALLY SIGNIFICANT PSYCHOTROPIC DRUG-DRUG INTERACTIONS IN THE PRIMARY CARE SETTING

PubMed Central

English, Brett A.; Dortch, Marcus; Ereshefsky, Larry; Jhee, Stanford

2014-01-01

In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug’s pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. PMID:22707017

Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort?

PubMed

Mouly, Stéphane; Lloret-Linares, Célia; Sellier, Pierre-Olivier; Sene, Damien; Bergmann, J-F

2017-04-01

An interaction of drug with food, herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John's Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient' and doctor's information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio. Copyright © 2016 Elsevier Ltd. All rights reserved.

Clinically relevant safety issues associated with St. John's wort product labels.

PubMed

Clauson, Kevin A; Santamarina, Marile L; Rutledge, Jennifer C

2008-07-17

St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA. Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings. Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of a priori safety issues included on a product label was 1.91 (range 0-8) for 23.9% completeness. The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues which could enhance the quality of counseling by HCPs and health store clerks. HCPs and consumers may benefit if the FDA re-examined labeling requirements for dietary supplements.

Clinically relevant safety issues associated with St. John's wort product labels

PubMed Central

Clauson, Kevin A; Santamarina, Marile L; Rutledge, Jennifer C

2008-01-01

Background St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA. Methods Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings. Results Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of a priori safety issues included on a product label was 1.91 (range 0–8) for 23.9% completeness. Conclusion The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues which could enhance the quality of counseling by HCPs and health store clerks. HCPs and consumers may benefit if the FDA re-examined labeling requirements for dietary supplements. PMID:18637192

Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents.

PubMed

Rong, Carola; Carmona, Nicole E; Lee, Yena L; Ragguett, Renee-Marie; Pan, Zihang; Rosenblat, Joshua D; Subramaniapillai, Mehala; Shekotikhina, Margarita; Almatham, Fahad; Alageel, Asem; Mansur, Rodrigo; Ho, Roger C; McIntyre, Roger S

2018-01-01

To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper. Expert opinion: Δ 9 -Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Integrating Anatomy Training into Radiation Oncology Residency: Considerations for Developing a Multidisciplinary, Interactive Learning Module for Adult Learners

ERIC Educational Resources Information Center

Labranche, Leah; Johnson, Marjorie; Palma, David; D'Souza, Leah; Jaswal, Jasbir

2015-01-01

Radiation oncologists require an in-depth understanding of anatomical relationships for modern clinical practice, although most do not receive formal anatomy training during residency. To fulfill the need for instruction in relevant anatomy, a series of four multidisciplinary, interactive learning modules were developed for a cohort of radiation…

Multiple Levels of Suffering: Discrimination in Health-Care Settings is Associated With Enhanced Laboratory Pain Sensitivity in Sickle Cell Disease.

PubMed

Mathur, Vani A; Kiley, Kasey B; Haywood, Carlton; Bediako, Shawn M; Lanzkron, Sophie; Carroll, C Patrick; Buenaver, Luis F; Pejsa, Megan; Edwards, Robert R; Haythornthwaite, Jennifer A; Campbell, Claudia M

2016-12-01

People living with sickle cell disease (SCD) experience severe episodic and chronic pain and frequently report poor interpersonal treatment within health-care settings. In this particularly relevant context, we examined the relationship between perceived discrimination and both clinical and laboratory pain. Seventy-one individuals with SCD provided self-reports of experiences with discrimination in health-care settings and clinical pain severity, and completed a psychophysical pain testing battery in the laboratory. Discrimination in health-care settings was correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, as well as stress, depression, and sleep. After controlling for relevant covariates, discrimination remained a significant predictor of mechanical temporal summation (a marker of central pain facilitation), but not clinical pain severity or suprathreshold heat pain response. Furthermore, a significant interaction between experience with discrimination and clinical pain severity was associated with mechanical temporal summation; increased experience with discrimination was associated with an increased correlation between clinical pain severity and temporal summation of pain. Perceived discrimination within health-care settings was associated with pain facilitation. These findings suggest that discrimination may be related to increased central sensitization among SCD patients, and more broadly that health-care social environments may interact with pain pathophysiology.

Evaluation of linear classifiers on articles containing pharmacokinetic evidence of drug-drug interactions.

PubMed

Kolchinsky, A; Lourenço, A; Li, L; Rocha, L M

2013-01-01

Drug-drug interaction (DDI) is a major cause of morbidity and mortality. DDI research includes the study of different aspects of drug interactions, from in vitro pharmacology, which deals with drug interaction mechanisms, to pharmaco-epidemiology, which investigates the effects of DDI on drug efficacy and adverse drug reactions. Biomedical literature mining can aid both kinds of approaches by extracting relevant DDI signals from either the published literature or large clinical databases. However, though drug interaction is an ideal area for translational research, the inclusion of literature mining methodologies in DDI workflows is still very preliminary. One area that can benefit from literature mining is the automatic identification of a large number of potential DDIs, whose pharmacological mechanisms and clinical significance can then be studied via in vitro pharmacology and in populo pharmaco-epidemiology. We implemented a set of classifiers for identifying published articles relevant to experimental pharmacokinetic DDI evidence. These documents are important for identifying causal mechanisms behind putative drug-drug interactions, an important step in the extraction of large numbers of potential DDIs. We evaluate performance of several linear classifiers on PubMed abstracts, under different feature transformation and dimensionality reduction methods. In addition, we investigate the performance benefits of including various publicly-available named entity recognition features, as well as a set of internally-developed pharmacokinetic dictionaries. We found that several classifiers performed well in distinguishing relevant and irrelevant abstracts. We found that the combination of unigram and bigram textual features gave better performance than unigram features alone, and also that normalization transforms that adjusted for feature frequency and document length improved classification. For some classifiers, such as linear discriminant analysis (LDA), proper dimensionality reduction had a large impact on performance. Finally, the inclusion of NER features and dictionaries was found not to help classification.

The effect of grapefruit juice on drug disposition

PubMed Central

Hanley, Michael J.; Cancalon, Paul; Widmer, Wilbur W.; Greenblatt, David J.

2011-01-01

Introduction Since their initial discovery in 1989, grapefruit juice-drug interactions have received extensive interest from the scientific, medical, regulatory, and lay communities. Although knowledge regarding the effects of grapefruit juice on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. Areas covered This article reviews the in vitro effects of grapefruit juice and its constituents on the activity of cytochrome P450 enzymes, organic anion-transporting polypeptides, P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported area under the plasma concentration-time curve ratios for available grapefruit juice-drug interaction studies are also provided. Relevant investigations were identified by searching the Pubmed electronic database from 1989 to 2010. Expert opinion Grapefruit juice increases the bioavailability of some orally-administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, grapefruit juice can decrease the oral absorption of a few drugs that rely on organic anion-transporting polypeptides in the gastrointestinal tract for their uptake. The number of drugs shown to interact with grapefruit juice in vitro is far greater than the number of clinically relevant grapefruit juice-drug interactions. For the majority of patients, complete avoidance of grapefruit juice is unwarranted. PMID:21254874

Nonlinear Directed Interactions Between HRV and EEG Activity in Children With TLE.

PubMed

Schiecke, Karin; Pester, Britta; Piper, Diana; Benninger, Franz; Feucht, Martha; Leistritz, Lutz; Witte, Herbert

2016-12-01

Epileptic seizure activity influences the autonomic nervous system (ANS) in different ways. Heart rate variability (HRV) is used as indicator for alterations of the ANS. It was shown that linear, nondirected interactions between HRV and EEG activity before, during, and after epileptic seizure occur. Accordingly, investigations of directed nonlinear interactions are logical steps to provide, e.g., deeper insight into the development of seizure onsets. Convergent cross mapping (CCM) investigates nonlinear, directed interactions between time series by using nonlinear state space reconstruction. CCM is applied to simulated and clinically relevant data, i.e., interactions between HRV and specific EEG components of children with temporal lobe epilepsy (TLE). In addition, time-variant multivariate Autoregressive model (AR)-based estimation of partial directed coherence (PDC) was performed for the same data. Influence of estimation parameters and time-varying behavior of CCM estimation could be demonstrated by means of simulated data. AR-based estimation of PDC failed for the investigation of our clinical data. Time-varying interval-based application of CCM on these data revealed directed interactions between HRV and delta-related EEG activity. Interactions between HRV and alpha-related EEG activity were visible but less pronounced. EEG components mainly drive HRV. The interaction pattern and directionality clearly changed with onset of seizure. Statistical relevant interactions were quantified by bootstrapping and surrogate data approach. In contrast to AR-based estimation of PDC CCM was able to reveal time-courses and frequency-selective views of nonlinear interactions for the further understanding of complex interactions between the epileptic network and the ANS in children with TLE.

[Is combining metronidazole and alcohol really hazardous?].

PubMed

Fjeld, Hilde; Raknes, Guttorm

2014-09-16

It is common practice to warn against intake of alcohol (ethanol) when taking metronidazole because of the risk of an effect similar to disulfiram (Antabuse). In this article we investigate whether such a warning has any real basis. KNOWLEDGE BASE: The article is based on a review of relevant literature retrieved through a search in PubMed. A search was also made in the WHO's database on adverse effects. No in-vitro studies, animal models, reports of adverse effects or clinical studies provide any convincing evidence of a disulfiram-like interaction between ethanol and metronidazole. The warning against simultaneous use of alcohol and metronidazole appear to be based on laboratory experiments and individual case histories in which the reported reactions are equally likely to have been caused by ethanol alone or by adverse effects of metronidazole. Recent research does not confirm a clinically relevant interaction between ethanol and metronidazole.

Virus-Bacteria Interactions: Implications and Potential for the Applied and Agricultural Sciences.

PubMed

Moore, Matthew D; Jaykus, Lee-Ann

2018-02-02

Eukaryotic virus-bacteria interactions have recently become an emerging topic of study due to multiple significant examples related to human pathogens of clinical interest. However, such omnipresent and likely important interactions for viruses and bacteria relevant to the applied and agricultural sciences have not been reviewed or compiled. The fundamental basis of this review is that these interactions have importance and deserve more investigation, as numerous potential consequences and applications arising from their discovery are relevant to the applied sciences. The purpose of this review is to highlight and summarize eukaryotic virus-bacteria findings in the food/water, horticultural, and animal sciences. In many cases in the agricultural sciences, mechanistic understandings of the effects of virus-bacteria interactions remain unstudied, and many studies solely focus on co-infections of bacterial and viral pathogens. Given recent findings relative to human viral pathogens, further research related to virus-bacteria interactions would likely result in numerous discoveries and beneficial applications.

Caspofungin exposure alters the core septin AspB interactome of Aspergillus fumigatus.

PubMed

Vargas-Muñiz, José M; Renshaw, Hilary; Waitt, Greg; Soderblom, Erik J; Moseley, M Arthur; Palmer, Jonathan M; Juvvadi, Praveen R; Keller, Nancy P; Steinbach, William J

2017-04-01

Aspergillus fumigatus, the main etiological agent of invasive aspergillosis, is a leading cause of death in immunocompromised patients. Septins, a conserved family of GTP-binding proteins, serve as scaffolding proteins to recruit enzymes and key regulators to different cellular compartments. Deletion of the A. fumigatus septin aspB increases susceptibility to the echinocandin antifungal caspofungin. However, how AspB mediates this response to caspofungin is unknown. Here, we characterized the AspB interactome under basal conditions and after exposure to a clinically relevant concentration of caspofungin. While A. fumigatus AspB interacted with 334 proteins, including kinases, cell cycle regulators, and cell wall synthesis-related proteins under basal growth conditions, caspofungin exposure altered AspB interactions. A total of 69 of the basal interactants did not interact with AspB after exposure to caspofungin, and 54 new interactants were identified following caspofungin exposure. We generated A. fumigatus deletion strains for 3 proteins (ArpB, Cyp4, and PpoA) that only interacted with AspB following exposure to caspofungin that were previously annotated as induced after exposure to antifungal agents, yet only PpoA was implicated in the response to caspofungin. Taken together, we defined how the septin AspB interactome is altered in the presence of a clinically relevant antifungal. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparative laser-tissue interaction effects at 1.96 and 2.01 um of Cr; Tm:YAG laser

NASA Astrophysics Data System (ADS)

Pankratov, Michail M.; Perrault, Donald F., Jr.; Shapshay, Stanley M.; Pinto, Joseph F.; Esterowitz, Dina; Aretz, H. Thomas

1992-08-01

A pulsed spiking and nonspiking Cr; thulium (Tm):YAG flash lamp pumped laser operating at 1.96 and 2.01 μm was investigated in vitro in the clinically relevant power range for its basic laser-tissue interaction with soft, cartilaginous, and bone tissues. Some explanations of the differences and possible medical applications are discussed.

Education research: communication skills for neurology residents: structured teaching and reflective practice.

PubMed

Watling, Christopher J; Brown, Judith B

2007-11-27

Despite the importance of communication skills for neurologists, specific training in this area at the residency level is often lacking. This study aimed to enhance learning of these skills and to encourage reflective practice around communication skills. A group of 12 neurology residents participated in a series of six case-based communication skills workshops. Each workshop focused on a particular clinical scenario, including breaking bad news, discussing do-not-resuscitate orders, communicating with "difficult" patients, disclosing medical errors, obtaining informed consent for neurologic tests and procedures, and discussing life-and-death decisions with families of critically ill patients. Residents also kept reflective portfolios in which real examples of these interactions were recorded. The program was well accepted, and residents rated the workshops as effective and relevant to their practice. Analysis of residents' portfolios revealed three themes relevant to patient-physician communication: 1) communication is more successful when adequate time is allowed, 2) the ability to empathize with patients and their families is essential to successful interactions, and 3) the development of specific approaches to challenging scenarios can facilitate effective interactions. The portfolios also demonstrated that residents would engage in reflective practice. Targeting of communication skills training around specific clinical scenarios using neurologic cases was well accepted and was deemed relevant to practice. The use of portfolios may promote lifelong learning in this area.

Biology of acute lymphoblastic leukemia (ALL): clinical and therapeutic relevance.

PubMed

Graux, Carlos

2011-04-01

Acute lymphoblastic leukemia is a heterogeneous disease comprising several clinico-biological entities. Karyotyping of leukemic cells identifies recurrent chromosome rearrangements. These are usually translocations that activate genes encoding transcription factor regulating B- or T-cell differentiation. Gene expression-array confirms the prognostic relevance of ALL subgroups identified by specific chromosomal rearrangements and isolates new subgroups. Analysis of genomic copy number changes and high throughput sequencing reveal new cryptic deletions. The challenge is now to understand how these cooperative genetic lesions interact in order to have the molecular rationales needed to select new therapeutic targets and to develop and combine inhibitors with high levels of anti-leukemic specificity. The aim of this paper is to provide some data on the biology of acute lymphoblastic leukemia which are relevant in clinical practice. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain. Preclinical overview].

PubMed

Tzschentke, T M; Christoph, T; Schröder, W; Englberger, W; De Vry, J; Jahnel, U; Kögel, B Y

2011-02-01

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

Direct Acting Anti-hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction

PubMed Central

Geddawy, Ayman; Ibrahim, Yasmine F.; Elbahie, Nabil M.; Ibrahim, Mohammad A.

2017-01-01

Abstract Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The introduction of direct acting antiviral agents (DAAs) for its treatment represents a major advance in terms of sustained virologic response (SVR) rates and adverse effect profiles. Mechanistically, DAAs inhibit specific HCV non-structural proteins (NS) that are vital for its replication. Boceprevir, telaprevir, simeprevir, asunaprevir, grazoprevir and paritaprevir are NS3/4A inhibitors. Ombitasvir, ledipasvir, daclatasvir, elbasvir and velpatasvir are NS5A inhibitors. Sofosbuvir and dasabuvir are NS5B inhibitors. Currently, a combination of two or more DAAs is the corner stone for the treatment of HCV infection. However, the success of DAA therapy is facing several challenges, including the potential of drug-drug interactions and resistant variance. Moreover, the shortage of relevant clinical pharmacological data and drug interaction regarding DAA is a clinical concern. The present review discusses the clinical pharmacology of DAAs with special emphasis on drug-drug interaction. PMID:28680834

Drug Interactions with Lithium: An Update.

PubMed

Finley, Patrick R

2016-08-01

Lithium has been used for the management of psychiatric illnesses for over 50 years and it continues to be regarded as a first-line agent for the treatment and prevention of bipolar disorder. Lithium possesses a narrow therapeutic index and comparatively minor alterations in plasma concentrations can have significant clinical sequelae. Several drug classes have been implicated in the development of lithium toxicity over the years, including diuretics and non-steroidal anti-inflammatory compounds, but much of the anecdotal and experimental evidence supporting these interactions is dated, and many newer medications and medication classes have been introduced during the intervening years. This review is intended to provide an update on the accumulated evidence documenting potential interactions with lithium, with a focus on pharmacokinetic insights gained within the last two decades. The clinical relevance and ramifications of these interactions are discussed.

Direct and indirect risk associated with the use of dietary supplements among persons with dementia in a Norwegian memory clinic.

PubMed

Risvoll, Hilde; Giverhaug, Trude; Halvorsen, Kjell H; Waaseth, Marit; Musial, Frauke

2017-05-12

The use of dietary supplements (DS) is common among persons with dementia. Direct risks associated with DS use include adverse events and DS-drug interactions. A direct risk is a risk caused by the treatment itself. Indirect risks are related to the treatment setting, such as the conditions of use, and not to the treatment itself. Because dementia symptoms may reduce a person's ability to cope with the administration of DS, the use of DS may pose a threat to safety as an indirect risk. The aim of this study was to describe the extent of DS use among persons with dementia in ambulatory care and to identify some relevant direct and indirect risks related to DS use. We conducted a survey among 151 persons with dementia attending an outpatient memory clinic in Northern Norway. Study measurements included: the participants' characteristics, cognitive functioning, functioning in the activities of daily living (ADL), and the use of DS and prescription drugs (PD). We assessed direct risks by evaluating potential DS-drug interactions and indirect risks by evaluating the conditions under which it was used. Forty-six percent (n = 70) of the persons with dementia used DS. Ninety-seven percent (n = 147) used PD. We found potentially clinically relevant DS-drug interactions representing a direct risk in eight persons with dementia (11% of users). While only 36% (n = 26) of the participants received assistance with the administration of DS, 73% (n = 106) received assistance with the administration of PD. Persons with dementia living alone were at risk of not receiving assistance, as home care service seldom was involved in DS administration. Data indicated that assistance with DS administration was not provided for all persons with dementia in need, representing an indirect risk to these persons. Only one-third of the persons with dementia and half of the caregivers were aware of the general risks of adverse events and interactions associated with the use of DS. Persons with dementia use DS frequently, yet DS use may be associated with direct and indirect risks to patient safety as potentially clinically relevant interactions were discovered and DS intake often was unsupervised.

Clinical concentrations of chemically diverse general anesthetics minimally affect lipid bilayer properties.

PubMed

Herold, Karl F; Sanford, R Lea; Lee, William; Andersen, Olaf S; Hemmings, Hugh C

2017-03-21

General anesthetics have revolutionized medicine by facilitating invasive procedures, and have thus become essential drugs. However, detailed understanding of their molecular mechanisms remains elusive. A mechanism proposed over a century ago involving unspecified interactions with the lipid bilayer known as the unitary lipid-based hypothesis of anesthetic action, has been challenged by evidence for direct anesthetic interactions with a range of proteins, including transmembrane ion channels. Anesthetic concentrations in the membrane are high (10-100 mM), however, and there is no experimental evidence ruling out a role for the lipid bilayer in their ion channel effects. A recent hypothesis proposes that anesthetic-induced changes in ion channel function result from changes in bilayer lateral pressure that arise from partitioning of anesthetics into the bilayer. We examined the effects of a broad range of chemically diverse general anesthetics and related nonanesthetics on lipid bilayer properties using an established fluorescence assay that senses drug-induced changes in lipid bilayer properties. None of the compounds tested altered bilayer properties sufficiently to produce meaningful changes in ion channel function at clinically relevant concentrations. Even supra-anesthetic concentrations caused minimal bilayer effects, although much higher (toxic) concentrations of certain anesthetic agents did alter lipid bilayer properties. We conclude that general anesthetics have minimal effects on bilayer properties at clinically relevant concentrations, indicating that anesthetic effects on ion channel function are not bilayer-mediated but rather involve direct protein interactions.

A Model of Auditory-Cognitive Processing and Relevance to Clinical Applicability.

PubMed

Edwards, Brent

2016-01-01

Hearing loss and cognitive function interact in both a bottom-up and top-down relationship. Listening effort is tied to these interactions, and models have been developed to explain their relationship. The Ease of Language Understanding model in particular has gained considerable attention in its explanation of the effect of signal distortion on speech understanding. Signal distortion can also affect auditory scene analysis ability, however, resulting in a distorted auditory scene that can affect cognitive function, listening effort, and the allocation of cognitive resources. These effects are explained through an addition to the Ease of Language Understanding model. This model can be generalized to apply to all sounds, not only speech, representing the increased effort required for auditory environmental awareness and other nonspeech auditory tasks. While the authors have measures of speech understanding and cognitive load to quantify these interactions, they are lacking measures of the effect of hearing aid technology on auditory scene analysis ability and how effort and attention varies with the quality of an auditory scene. Additionally, the clinical relevance of hearing aid technology on cognitive function and the application of cognitive measures in hearing aid fittings will be limited until effectiveness is demonstrated in real-world situations.

Clinical Correlations as a Tool in Basic Science Medical Education

PubMed Central

Klement, Brenda J.; Paulsen, Douglas F.; Wineski, Lawrence E.

2016-01-01

Clinical correlations are tools to assist students in associating basic science concepts with a medical application or disease. There are many forms of clinical correlations and many ways to use them in the classroom. Five types of clinical correlations that may be embedded within basic science courses have been identified and described. (1) Correlated examples consist of superficial clinical information or stories accompanying basic science concepts to make the information more interesting and relevant. (2) Interactive learning and demonstrations provide hands-on experiences or the demonstration of a clinical topic. (3) Specialized workshops have an application-based focus, are more specialized than typical laboratory sessions, and range in complexity from basic to advanced. (4) Small-group activities require groups of students, guided by faculty, to solve simple problems that relate basic science information to clinical topics. (5) Course-centered problem solving is a more advanced correlation activity than the others and focuses on recognition and treatment of clinical problems to promote clinical reasoning skills. Diverse teaching activities are used in basic science medical education, and those that include clinical relevance promote interest, communication, and collaboration, enhance knowledge retention, and help develop clinical reasoning skills. PMID:29349328

[Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

PubMed

Martínez-Múgica, Cristina

2015-12-01

Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

Current transcatheter devices to treat functional tricuspid regurgitation with discussion of issues relevant to clinical trial design

PubMed Central

2017-01-01

Functional or secondary tricuspid regurgitation (TR) has seen increased attention in recent times as relationships with clinically-relevant outcomes have come to light. Despite the association of increased mortality with significant TR, the disease remains under-recognized and thus relatively untreated. In addition, the disease itself has not been extensively studied and the interactions between annular dilatation, right heart disease and pulmonary hypertension are poorly understood. However, the high mortality and recurrence rate with current surgical replacement or repair techniques is well recognised, opening the door to transcatheter therapies for functional TR. The current perspective reviews the rationale for transcatheter solutions, describes some of the current approaches and discusses the ongoing questions of a poorly-studied condition which may limit the design of clinical trials for this disease. PMID:28706866

Interactions of bilastine, a new oral H₁ antihistamine, with human transporter systems.

PubMed

Lucero, Maria Luisa; Gonzalo, Ana; Ganza, Alvaro; Leal, Nerea; Soengas, Itziar; Ioja, Eniko; Gedey, Szilvia; Jahic, Mirza; Bednarczyk, Dallas

2012-06-01

Membrane transporters play a significant role in facilitating transmembrane drug movement. For new pharmacological agents, it is important to evaluate potential interactions (e.g., substrate specificity and/or inhibition) with human transporters that may affect their pharmacokinetics, efficacy, or toxicity. Bilastine is a new nonsedating H₁ antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The in vitro inhibitory effects of bilastine were assessed on 12 human transporters: four efflux [multidrug resistance protein 1 (MDR1) or P-glycoprotein, breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), and bile salt export pump) and eight uptake transporters (sodium taurocholate cotransporting polypeptide, organic cation transporter (OCT)1, organic anion transporter (OAT)1, OAT3, OCT2, OATP2B1, OATP1B1, and OATP1B3). Only mild inhibition was found for MDR1-, OCT1-, and OATP2B1-mediated transport of probe substrates at the highest bilastine concentration assayed (300 μM; half-maximal inhibitory concentration: ≥300 μM). Bilastine transport by MDR1, BCRP, OAT1, OAT3, and OCT2 was also investigated in vitro. Only MDR1 active transport of bilastine was relevant, whereas it did not appear to be a substrate of OCT2, OAT1, or OAT3, nor was it transported substantially by BCRP. Drug-drug interactions resulting from bilastine inhibition of drug transporters that would be generally regarded as clinically relevant are unlikely. Additionally, bilastine did not appear to be a substrate of human BCRP, OAT1, OAT3, or OCT2 and thus is not a potential victim of inhibitors of these transporters. On the other hand, based on in vitro evaluation, clinically relevant interactions with MDR1 inhibitors are anticipated.

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

PubMed

Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

2017-08-01

A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

The pragmatics of therapeutic interaction: an empirical study.

PubMed

Lepper, Georgia

2009-10-01

The research reported in this article aims to demonstrate a method for the systematic study of the therapist/patient interaction in psychoanalytic psychotherapy, drawing upon the tradition and methods of 'pragmatics'--the study of language in interaction. A brief introduction to the discipline of pragmatics demonstrates its relevance to the contemporary focus of clinical theory on the here-and-now dynamics of the relationship between analyst and patient. This is followed by a detailed study of five segments from the transcript of a therapeutic dialogue, drawn from a brief psychoanalytic psychotherapy, in which therapist and patient negotiate the meaning of the patient's symptom: Is it psychosomatic? The research seeks to show how the therapeutic process can be observed and studied as an interactional achievement, grounded in general and well-studied procedures through which meaning is intersubjectively developed and shared. Implications of the analysis for clinical theory and practice, and further research, are discussed.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.

PubMed

Boyce, Richard D; Horn, John R; Hassanzadeh, Oktie; Waard, Anita de; Schneider, Jodi; Luciano, Joanne S; Rastegar-Mojarad, Majid; Liakata, Maria

2013-01-26

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market.

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness

PubMed Central

2013-01-01

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market. PMID:23351881

Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?

PubMed Central

Cierpicki, Tomasz; Grembecka, Jolanta

2015-01-01

Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein-protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of pre-clinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of protein-protein interactions highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein-protein interfaces, with the goal to address ‘druggability’ of new PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new protein-protein interactions and evaluate prospects and limits of the research in this field. We conclude that not all PPIs are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new protein-protein interactions. PMID:25510283

Beyond immune checkpoint blockade: new approaches to targeting host-tumor interactions in prostate cancer: report from the 2014 Coffey-Holden prostate cancer academy meeting.

PubMed

Miyahira, Andrea K; Kissick, Haydn T; Bishop, Jennifer L; Takeda, David Y; Barbieri, Christopher E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2015-03-01

The 2014 Coffey-Holden Prostate Cancer Academy Meeting, held in La Jolla, CA from June 26 to 29, 2014, was themed: "Beyond Immune Checkpoint Blockade: New Approaches to Targeting Host-Tumor Interactions in Prostate Cancer." Sponsored by the Prostate Cancer Foundation (PCF), this annual, invitation-only meeting is structured as an action-tank, and brought together 72 investigators with diverse academic backgrounds to discuss the most relevant topics in the fields of prostate cancer immunotherapy and the tumor microenvironment. The questions addressed at the meeting included: mechanisms underlying the successes and failures of prostate cancer immunotherapies, how to trigger an effective immune response against prostate cancer, the tumor microenvironment and its role in therapy resistance and tumor metastasis, clinically relevant prostate cancer mouse models, how host-tumor interactions affect current therapies and tumor phenotypes, application of principles of precision medicine to prostate cancer immunotherapy, optimizing immunotherapy clinical trial design, and complex multi-system interactions that affect prostate cancer and immune responses including the effects of obesity and the potential role of the host microbiome. This article highlights the most significant recent progress and unmet needs that were discussed at the meeting toward the goal of speeding the development of optimal immunotherapies for the treatment of prostate cancer. © 2014 Wiley Periodicals, Inc.

As the medical education curriculum is changing, it is still good to train students and physicians in many different patient locations.

PubMed

Reynolds, Herbert Y

2014-12-01

Medical teaching methods are changing with students now encouraged to be self-learners, accruing more knowledge themselves, receiving less didactic instruction, utilizing more peer group interactions, and using more portable self-accessible technology to get medical information. Medical school curriculums are adapting with more simulated instruction, group analysis of clinical problems (problem-based learning), earlier exposure to patients and their evaluation, volunteer medical missions, and participation in relevant clinical research. But will these changes, especially the use of portable technology for retrieving medical information, enhance learning, and improve devising clinical strategy? To build clinical skills and confidence, it still seems relevant for the students and clinicians to evaluate patients in multiple locations under various circumstances. This is perhaps necessary during all phases of medical study, post-graduate training, research investigation, and in a medical career, including later phases when senior and elder faculty participate in medical teaching and/or provide health care. The emphasis of this perspective is to assess some of these clinical "settings" that reinforce learning skills and flexible clinical approaches.

Formulations in Psychotherapy: Admission Interviews and the Conversational Construction of Diagnosis.

PubMed

Bonnin, Juan Eduardo

2017-09-01

In this article, we contribute to understanding the interactional aspects of making clinical diagnosis in mental health care. We observe that therapists, during the "problem presentation" sequence in clinical encounters, often use a specific form of diagnostic formulations to elicit more diagnostically relevant information. By doing so, they often substitute one type of verb with another, following a diagnostic hypothesis. Specifically, in interviews that arrive at a diagnosis of neurosis, therapists formulate with behavioral verbal processes; in interviews that arrive at a diagnosis of psychosis, they do so with material ones. Such formulations often prove useful to define clinical diagnoses. They can, however, also be dangerous in that they may favor the therapist's agenda over the patient's. Our analysis helps therapists not only better understand the diagnostic process but also reflect upon their own use of diagnostic formulations and become aware of the clinical effects of their interactional performance.

The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations.

PubMed

Lee, HoJoon; Palm, Jennifer; Grimes, Susan M; Ji, Hanlee P

2015-10-27

The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history. The Cancer Genome Atlas Clinical Explorer enables the cancer research community and others to explore clinically relevant associations inferred from TCGA data. With its accessible web and mobile interface, users can examine queries and test hypothesis regarding genomic/proteomic alterations across a broad spectrum of malignancies.

Amnesia and crime: a neuropsychiatric response.

PubMed

Wortzel, Hal S; Arciniegas, David B

2008-01-01

Bourget and Whitehurst's "Amnesia and Crime," published in a prior issue of the Journal, addresses a conceptually complex and clinically challenging subject. Their treatment emphasizes psychiatric conditions in which memory disturbances may arise that are relevant to criminal proceedings. However, their consideration of the neurobiology of memory, memory disturbances, and the neurobiological bases of interactions between psychiatric symptoms and memory merit further elaboration. The relevance of memory impairment to criminal matters requires forensic psychiatric experts to possess a basic understanding of the phenomenology and neurobiology of memory. The present authors describe briefly the phenomenology and neuroanatomy of memory, emphasizing first that memory is not a unitary cognitive domain, clinically or neurobiologically. The assertion that psychotic delusions produce memory impairment is challenged, and the description of "organic" amnesia, both semantically and in terms of its clinical features, is reframed. Resources on which to build a neuropsychiatric foundation for forensic psychiatric opinions on memory impairment surrounding criminal behavior are offered.

Clinical concentrations of chemically diverse general anesthetics minimally affect lipid bilayer properties

PubMed Central

Herold, Karl F.; Sanford, R. Lea; Lee, William; Andersen, Olaf S.; Hemmings, Hugh C.

2017-01-01

General anesthetics have revolutionized medicine by facilitating invasive procedures, and have thus become essential drugs. However, detailed understanding of their molecular mechanisms remains elusive. A mechanism proposed over a century ago involving unspecified interactions with the lipid bilayer known as the unitary lipid-based hypothesis of anesthetic action, has been challenged by evidence for direct anesthetic interactions with a range of proteins, including transmembrane ion channels. Anesthetic concentrations in the membrane are high (10–100 mM), however, and there is no experimental evidence ruling out a role for the lipid bilayer in their ion channel effects. A recent hypothesis proposes that anesthetic-induced changes in ion channel function result from changes in bilayer lateral pressure that arise from partitioning of anesthetics into the bilayer. We examined the effects of a broad range of chemically diverse general anesthetics and related nonanesthetics on lipid bilayer properties using an established fluorescence assay that senses drug-induced changes in lipid bilayer properties. None of the compounds tested altered bilayer properties sufficiently to produce meaningful changes in ion channel function at clinically relevant concentrations. Even supra-anesthetic concentrations caused minimal bilayer effects, although much higher (toxic) concentrations of certain anesthetic agents did alter lipid bilayer properties. We conclude that general anesthetics have minimal effects on bilayer properties at clinically relevant concentrations, indicating that anesthetic effects on ion channel function are not bilayer-mediated but rather involve direct protein interactions. PMID:28265069

Evaluating Cardiovascular Health Disparities Using Estimated Race/Ethnicity: A Validation Study.

PubMed

Bykov, Katsiaryna; Franklin, Jessica M; Toscano, Michele; Rawlins, Wayne; Spettell, Claire M; McMahill-Walraven, Cheryl N; Shrank, William H; Choudhry, Niteesh K

2015-12-01

Methods of estimating race/ethnicity using administrative data are increasingly used to examine and target disparities; however, there has been no validation of these methods using clinically relevant outcomes. To evaluate the validity of the indirect method of race/ethnicity identification based on place of residence and surname for assessing clinically relevant outcomes. A total of 2387 participants in the Post-MI Free Rx Event and Economic Evaluation (MI FREEE) trial who had both self-reported and Bayesian Improved Surname Geocoding method (BISG)-estimated race/ethnicity information available. We used tests of interaction to compare differences in the effect of providing full drug coverage for post-MI medications on adherence and rates of major vascular events or revascularization for white and nonwhite patients based upon self-reported and indirect racial/ethnic assignment. The impact of full coverage on clinical events differed substantially when based upon self-identified race (HR=0.97 for whites, HR=0.65 for nonwhites; interaction P-value=0.05); however, it did not differ among race/ethnicity groups classified using indirect methods (HR=0.87 for white and nonwhites; interaction P-value=0.83). The impact on adherence was the same for self-reported and BISG-estimated race/ethnicity for 2 of the 3 medication classes studied. Quantitatively and qualitatively different results were obtained when indirectly estimated race/ethnicity was used, suggesting that these techniques may not accurately describe aspects of race/ethnicity related to actual health behaviors.

[Telepsychiatry provides new opportunities for the prevention and treatment of mental health disorders].

PubMed

Folker, Marie Paldam; Helverskov, Trine; Nielsen, Amalie Søgaard; Jørgensen, Ulla Skov; Larsen, John Teilmann

2018-04-23

Digital technologies in mental healthcare are envisioned to offer easier, faster and more cost-effective access to mental healthcare. The scope for integrating digital technology into mental healthcare is vast: video conferencing, developing novel treatments using interactive software, mobile applications, and sensor technologies. We outline technology-based interventions, which are relevant to clinical practice, and present the evidence base for using digital technology as well as emerging challenges for their implementation in clinical practice.

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients.

PubMed

Bruch, Brittany A; Singh, Sachinkumar B; Ramsey, Laura J; Starner, Timothy D

2018-05-01

This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction. © 2018 Wiley Periodicals, Inc.

Nature vs. nurture: two brothers with schizophrenia.

PubMed

Keltner, N L; James, C A; Darling, R J; Findley, L S; Oliver, K

2001-01-01

The nature vs. nurture argument as it pertains to two brothers. To explore the synergistic effects of heritability and environment in the cases of two brothers with schizophrenia. Review of the literature and the authors' clinical experience. The nature vs. nurture dichotomy may not be as relevant as looking at the interaction between these two forces.

Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions

PubMed Central

Bohets, H; Lavrijsen, K; Hendrickx, J; van Houdt, J; van Genechten, V; Verboven, P; Meuldermans, W; Heykants, J

2000-01-01

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility.Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5-hydroxytryptamine-4 receptors and which is largely without central depressant or antidopaminergic side-effects.The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated.The major in vitro metabolite of cisapride was formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the production of norcisapride.By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent.The mean apparent Km against cisapride was 8.6±3.5 μM (n=3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 μM; therefore it is unlikely that cisapride would inhibit the metabolism of co-administered drugs.In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism. PMID:10780971

Teaching the physician-manager role to psychiatric residents: development and implementation of a pilot curriculum.

PubMed

Stergiopoulos, Vicky; Maggi, Julie; Sockalingam, Sanjeev

2009-01-01

The authors describe a pilot physician-manager curriculum designed to address the learning needs of psychiatric residents in administrative psychiatry and health systems. The pilot curriculum includes a junior and a senior toolkit of four workshops each. The junior toolkit introduces postgraduate-year two (PGY-2) residents to the principles of teamwork, conflict resolution, quality improvement, and program planning and evaluation. The senior toolkit exposes PGY-4 residents to leadership and change management, organizational structures, mental health and addictions reform, and self and career development. Following curriculum implementation at the University of Toronto, residents rated the importance and clinical relevance of curriculum objectives and commented on the strengths and weaknesses of the workshops and areas needing improvement. The pilot curriculum was successfully introduced at the University of Toronto in 2006. Residents rated the curriculum very highly and commented that interactive learning and contextually relevant topics are essential in meeting their needs. It is possible to successfully introduce a physician-manager curriculum early during psychiatric residency training, to match the specific needs of clinical rotations. Interactive techniques and clinical illustrations may be crucial in facilitating teaching and learning the physician-manager role. The authors discuss barriers, facilitators, and critical success factors in implementing such a curriculum.

Clinical relevancy and determinants of potential drug–drug interactions in chronic kidney disease patients: results from a retrospective analysis

PubMed Central

Saleem, Ahsan; Masood, Imran; Khan, Tahir Mehmood

2017-01-01

Background Chronic kidney disease (CKD) alters the pharmacokinetic and pharmacodynamic responses of various renally excreted drugs and increases the risk of drug-related problems, such as drug–drug interactions. Objectives To assess the pattern, determinants, and clinical relevancy of potential drug–drug interactions (pDDIs) in CKD patients. Materials and methods This study retrospectively reviewed medical charts of all CKD patients admitted in the nephrology unit of a tertiary care hospital in Pakistan from January 2013 to December 2014. The Micromedex Drug-Reax® system was used to screen patient profiles for pDDIs, and IBM SPSS version 20 was used to carry out statistical analysis. Results We evaluated 209 medical charts and found pDDIs in nearly 78.5% CKD patients. Overall, 541 pDDIs were observed, of which, nearly 60.8% patients had moderate, 41.1% had minor, 27.8% had major, and 13.4% had contraindicated interactions. Among those interactions, 49.4% had good evidence, 44.0% had fair, 6.3% had excellent evidence, and 35.5% interactions had delayed onset of action. The potential adverse outcomes of pDDIs included postural hypotension, QT prolongation, ceftriaxone–calcium precipitation, cardiac arrhythmias, and reduction in therapeutic effectiveness. The occurrence of pDDIs was found strongly associated with the age of <60 years, number of prescribed medicines ≥5, hypertension, and the lengthy hospitalization of patients. Conclusion The occurrence of pDDIs was high in CKD patients. It was observed that CKD patients with an older age, higher number of prescribed medicines, lengthy hospitalization, and hypertension were at a higher risk of pDDIs. PMID:29354553

Studying the neurobiology of human social interaction: Making the case for ecological validity.

PubMed

Hogenelst, Koen; Schoevers, Robert A; aan het Rot, Marije

2015-01-01

With this commentary we make the case for an increased focus on the ecological validity of the measures used to assess aspects of human social functioning. Impairments in social functioning are seen in many types of psychopathology, negatively affecting the lives of psychiatric patients and those around them. Yet the neurobiology underlying abnormal social interaction remains unclear. As an example of human social neuroscience research with relevance to biological psychiatry and clinical psychopharmacology, this commentary discusses published experimental studies involving manipulation of the human brain serotonin system that included assessments of social behavior. To date, these studies have mostly been laboratory-based and included computer tasks, observations by others, or single-administration self-report measures. Most laboratory measures used so far inform about the role of serotonin in aspects of social interaction, but the relevance for real-life interaction is often unclear. Few studies have used naturalistic assessments in real life. We suggest several laboratory methods with high ecological validity as well as ecological momentary assessment, which involves intensive repeated measures in naturalistic settings. In sum, this commentary intends to stimulate experimental research on the neurobiology of human social interaction as it occurs in real life.

A facile fluorescent "turn-off" method for sensing paraquat based on pyranine-paraquat interaction

NASA Astrophysics Data System (ADS)

Zhao, Zuzhi; Zhang, Fengwei; Zhang, Zipin

2018-06-01

Development of a technically simple yet effective method for paraquat (PQ) detection is of great importance due to its high clinical and environmental relevance. In this study, we developed a pyranine-based fluorescent "turn-off" method for PQ sensing based on pyranine-PQ interaction. We investigated the dependence of analytical performance of this method on the experimental conditions, such as the ion strength, medium pH, and so on. Under the optimized conditions, the method is sensitive and selective, and could be used for PQ detection in real-world sample. This study essentially provides a readily accessible fluorescent system for PQ sensing which is cheap, robust, and technically simple, and it is envisaged to find more interesting clinical and environmental applications.

Prevalence and clinical impact of recreational drug consumption in people living with HIV on treatment: a cross-sectional study

PubMed Central

Zurita, Beatriz; Velasco, Cesar; Feliu, Anna; Gutierrez, Mar; Masip, Montserrat; Mangues, M Antonia

2017-01-01

Objectives Drug interactions, poor adherence to medication and high-risk sexual behaviour may occur in individuals with HIV using recreational drugs. Thus, we aimed to assess the prevalence of recreational drugs use and to explore its clinical impact in HIV patients on treatment. Methods Observational, cross sectional, study conducted in a 700 bed university hospital, Barcelona, Spain. A total of 208 adults living with HIV on treatment were included. A questionnaire was administered by clinical pharmacists, including evaluation of sociodemographic variables, past 12-month drug consumption, adherence to antiretrovirals (Simplified Medication Adherence Questionnaire) and high-risk sexual behaviour (condomless sex/multiple partners). Additional data were obtained from clinical records. Recreational drug-antiretroviral interactions were checked in reference databases. Prevalence was calculated for 5% precision and 95% CI. Crude and adjusted binary logistic regressions were performed to identify associations between recreational drug use and adherence problems, and between recreational drug use and high-risk sexual behaviour. Results From the overall sample, 92 participants (44.2%) consumed recreational drugs over the past 1 year. Of these, 44 (48.8%) had used different types of recreational drugs in this period. We detected 11 recreational substances, including sildenafil and nitrites. The most consumed drugs were: cannabis (68.5%), cocaine (45.5%), nitrites (31.5%), sildenafil (28.3) and ecstasy (19.6%). Relevant interactions occurred in 46 (50%) of the individuals consuming drugs. Recreational drug consumption was found to be related to adherence problems with antiretrovirals (OR: 2.51 (95% CI 1.32 to 4.77) p=0.005) and high-risk sexual behaviour (OR: 2.81 (95% CI 1.47 to 5.39) p=0.002). Conclusions Recreational drugs are frequently used by HIV patients on treatment. Classical drugs and new substances consumed in sexual context are usual. Recreational drug consumption interferes with several clinical outcomes, including potentially relevant interactions between drugs and antiretrovirals, adherence problems and high-risk sexual behaviour. Thus, there is the urgent need of implementing patient-centred care involving recreational drug consumption. PMID:28100565

OTC analgesics and drug interactions: clinical implications

PubMed Central

Fendrick, A Mark; Pan, Deborah E; Johnson, Grace E

2008-01-01

The risk of drug interactions with concurrent use of multiple medications is a clinically relevant issue. Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents. Of particular significance is the increased risk of upper abdominal gastrointestinal adverse events in patients who take traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This risk is dose dependent and further increased in patients who take more than one NSAID or use NSAIDs in combination with certain other medications. Some NSAIDs may also mitigate the antiplatelet benefits of aspirin and may increase blood pressure in patients with hypertension. Clinicians should be aware of potential drug interactions with OTC analgesics when prescribing new medications. Additionally, patients should be properly counseled on the appropriate and safe use of OTC analgesics. PMID:18257920

Drug-nutrient interactions: a broad view with implications for practice.

PubMed

Boullata, Joseph I; Hudson, Lauren M

2012-04-01

The relevance of drug?nutrient interactions in daily practice continues to grow with the widespread use of medication. Interactions can involve a single nutrient, multiple nutrients, food in general, or nutrition status. Mechanistically, drug?nutrient interactions occur because of altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion, as well as additive or antagonistic effects. Optimal patient care includes identifying, evaluating, and managing these interactions. This task can be supported by a systematic approach for categorizing interactions and rating their clinical significance. This review provides such a broad framework using recent examples, as well as some classic drug?nutrient interactions. Pertinent definitions are presented, as is a suggested approach for clinicians. This important and expanding subject will benefit tremendously from further clinician involvement. Copyright © 2012 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Clinical relevance of cimetidine drug interactions.

PubMed

Shinn, A F

1992-01-01

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

Hyperforin in St. John's wort drug interactions.

PubMed

Madabushi, Rajanikanth; Frank, Bruno; Drewelow, Bernd; Derendorf, Hartmut; Butterweck, Veronika

2006-03-01

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Demanding Patient or Demanding Encounter?: A Case Study of a Cancer Clinic

PubMed Central

Stacey, Clare Louise; Henderson, Stuart; MacArthur, Kelly R; Dohan, Daniel

2009-01-01

This paper explores the sociological relevance of demanding encounters between doctors and patients. Borrowing from Potter and McKinlay's (2005) reconceptualization of the doctor-patient relationship, we suggest an analytic shift away from `demanding patients' toward `demanding encounters'. Such a shift places provider-patient conflict within a broader sociocultural context, emphasizing constraints facing both doctor and patient as they interact in a clinical setting. Specifically, through an ethnographic study of doctor-patient interactions at the oncology clinic of a US University Hospital, we examine the respective influences of new information technologies and patient consumerism in the production of demanding encounters in oncology. Findings suggest that these interconnected socio-cultural realities, in tandem with patient tendencies to challenge physician judgment or expertise, play a role in demanding encounters. We conclude by considering the implications of demanding encounters for doctors, patients and healthcare organizations. PMID:19619924

Growth factor delivery: How surface interactions modulate release in vitro and in vivo

PubMed Central

King, William J.; Krebsbach, Paul H.

2013-01-01

Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases. PMID:22433783

Recommendations for Selecting Drug-Drug Interactions for Clinical Decision Support

PubMed Central

Tilson, Hugh; Hines, Lisa E.; McEvoy, Gerald; Weinstein, David M.; Hansten, Philip D.; Matuszewski, Karl; le Comte, Marianne; Higby-Baker, Stefanie; Hanlon, Joseph T.; Pezzullo, Lynn; Vieson, Kathleen; Helwig, Amy L.; Huang, Shiew-Mei; Perre, Anthony; Bates, David W.; Poikonen, John; Wittie, Michael A.; Grizzle, Amy J.; Brown, Mary; Malone, Daniel C.

2016-01-01

Purpose To recommend principles for including drug-drug interactions (DDIs) in clinical decision support. Methods A conference series was conducted to improve clinical decision support (CDS) for DDIs. The Content Workgroup met monthly by webinar from January 2013 to February 2014, with two in-person meetings to reach consensus. The workgroup consisted of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information (IT) vendors, and healthcare organizations. Workgroup members addressed four key questions: (1) What process should be used to develop and maintain a standard set of DDIs?; (2) What information should be included in a knowledgebase of standard DDIs?; (3) Can/should a list of contraindicated drug pairs be established?; and (4) How can DDI alerts be more intelligently filtered? Results To develop and maintain a standard set of DDIs for CDS in the United States, we recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated, as only a small set of drug combinations are truly contraindicated. Finally, we recommend more research to identify methods to safely reduce repetitive and less relevant alerts. Conclusion A systematic ongoing process is necessary to select DDIs for alerting clinicians. We anticipate that our recommendations can lead to consistent and clinically relevant content for interruptive DDIs, and thus reduce alert fatigue and improve patient safety. PMID:27045070

An Overview of the Evidence and Mechanisms of Herb–Drug Interactions

PubMed Central

Fasinu, Pius S.; Bouic, Patrick J.; Rosenkranz, Bernd

2012-01-01

Despite the lack of sufficient information on the safety of herbal products, their use as alternative and/or complementary medicine is globally popular. There is also an increasing interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug interaction (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. Various mechanisms of pharmacokinetic HDI have been identified and include the alteration in the gastrointestinal functions with consequent effects on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic pharmacologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications. PMID:22557968

Autism and Related Disorders

PubMed Central

McPartland, James; Volkmar, Fred R.

2012-01-01

The Pervasive Developmental Disorders are a group of neurodevelopmental disorders that include Autistic Disorder, Asperger’s Disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Childhood Disintegrative Disorder (CDD), and Rett’s Disorder. All feature childhood onset with a constellation of symptoms spanning social interaction and communication and including atypical behavior patterns. The first three disorders (Autistic Disorder, Asperger’s Disorder, and PDD-NOS) are currently referred to as Autism Spectrum Disorders, reflecting divergent phenotypic and etiologic characteristics compared to Rett’s Disorder and CDD. This chapter reviews relevant research and clinical information relevant to appropriate medical diagnosis and treatment. PMID:22608634

Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review.

PubMed

Kotlinska-Lemieszek, Aleksandra; Klepstad, Pål; Haugen, Dagny Faksvåg

2015-01-01

Opioids are the most frequently used drugs to treat pain in cancer patients. In some patients, however, opioids can cause adverse effects and drug-drug interactions. No advice concerning the combination of opioids and other drugs is given in the current European guidelines. To identify studies that report clinically significant drug-drug interactions involving opioids used for pain treatment in adult cancer patients. Systematic review with searches in Embase, MEDLINE, and Cochrane Central Register of Controlled Trials from the start of the databases (Embase from 1980) through January 2014. In addition, reference lists of relevant full-text papers were hand-searched. Of 901 retrieved papers, 112 were considered as potentially eligible. After full-text reading, 17 were included in the final analysis, together with 15 papers identified through hand-searching of reference lists. All of the 32 included publications were case reports or case series. Clinical manifestations of drug-drug interactions involving opioids were grouped as follows: 1) sedation and respiratory depression, 2) other central nervous system symptoms, 3) impairment of pain control and/or opioid withdrawal, and 4) other symptoms. The most common mechanisms eliciting drug-drug interactions were alteration of opioid metabolism by inhibiting the activity of cytochrome P450 3A4 and pharmacodynamic interactions due to the combined effect on opioid, dopaminergic, cholinergic, and serotonergic activity in the central nervous system. Evidence for drug-drug interactions associated with opioids used for pain treatment in cancer patients is very limited. Still, the cases identified in this systematic review give some important suggestions for clinical practice. Physicians prescribing opioids should recognize the risk of drug-drug interactions and if possible avoid polypharmacy.

Clinical metabolomics paves the way towards future healthcare strategies

PubMed Central

Collino, Sebastiano; Martin, François‐Pierre J.; Rezzi, Serge

2013-01-01

Metabolomics is recognized as a powerful top‐down system biological approach to understand genetic‐environment‐health paradigms paving new avenues to identify clinically relevant biomarkers. It is nowadays commonly used in clinical applications shedding new light on physiological regulatory processes of complex mammalian systems with regard to disease aetiology, diagnostic stratification and, potentially, mechanism of action of therapeutic solutions. A key feature of metabolomics lies in its ability to underpin the complex metabolic interactions of the host with its commensal microbial partners providing a new way to define individual and population phenotypes. This review aims at describing recent applications of metabolomics in clinical fields with insight into diseases, diagnostics/monitoring and improvement of homeostatic metabolic regulation. PMID:22348240

Budding off: bringing functional genomics to Candida albicans

PubMed Central

Anderson, Matthew Z.

2016-01-01

Candida species are the most prevalent human fungal pathogens, with Candida albicans being the most clinically relevant species. Candida albicans resides as a commensal of the human gastrointestinal tract but is a frequent cause of opportunistic mucosal and systemic infections. Investigation of C. albicans virulence has traditionally relied on candidate gene approaches, but recent advances in functional genomics have now facilitated global, unbiased studies of gene function. Such studies include comparative genomics (both between and within Candida species), analysis of total RNA expression, and regulation and delineation of protein–DNA interactions. Additionally, large collections of mutant strains have begun to aid systematic screening of clinically relevant phenotypes. Here, we will highlight the development of functional genomics in C. albicans and discuss the use of these approaches to addressing both commensalism and pathogenesis in this species. PMID:26424829

Sex Differences in Androgen Regulation of Metabolism in Nonhuman Primates.

PubMed

True, Cadence; Abbott, David H; Roberts, Charles T; Varlamov, Oleg

2017-01-01

The in-depth characterization of sex differences relevant to human physiology requires the judicious use of a variety of animal models and human clinical data. Nonhuman primates (NHPs) represent an important experimental system that bridges rodent studies and clinical investigations. NHP studies have been especially useful in understanding the role of sex hormones in development and metabolism and also allow the elucidation of the effects of pertinent dietary influences on physiology pertinent to disease states such as obesity and diabetes. This chapter summarizes the current state of our understanding of androgen effects on male and female NHP metabolism relevant to hypogonadism in human males and polycystic ovary syndrome in human females. This review will also focus on the interaction between altered androgen levels and dietary restriction and excess, in particular the Western-style diet that underlies significant human pathophysiology.

SEX DIFFERENCES IN ANDROGEN REGULATION OF METABOLISM IN NONHUMAN PRIMATES

PubMed Central

True, Cadence; Abbott, David H.; Roberts, Charles T.; Varlamov, Oleg

2018-01-01

The in-depth characterization of sex differences relevant to human physiology requires the judicious use of a variety of animal models and human clinical data. Nonhuman primates (NHPs) represent an important experimental system that bridges rodent studies and clinical investigations. NHP studies have been especially useful in understanding the role of sex hormones in development and metabolism and also allow the elucidation of the effects of pertinent dietary influences on physiology pertinent to disease states such as obesity and diabetes. This chapter summarizes the current state of our understanding of androgen effects on male and female NHP metabolism relevant to hypogonadism in human males and polycystic ovary syndrome in human females, as well as the interaction between altered androgen levels and dietary restriction and excess, in particular the western-style diet that underlies significant human pathophysiology. PMID:29224110

Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects.

PubMed

Hausner, Helene; Derving Karsbøl, Julie; Holst, Anders G; Jacobsen, Jacob B; Wagner, Frank-Dietrich; Golor, Georg; Anderson, Thomas W

2017-11-01

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Profiling of 3696 Nuclear Receptor-Coregulator Interactions: A Resource for Biological and Clinical Discovery.

PubMed

Broekema, Marjoleine F; Hollman, Danielle A A; Koppen, Arjen; van den Ham, Henk-Jan; Melchers, Diana; Pijnenburg, Dirk; Ruijtenbeek, Rob; van Mil, Saskia W C; Houtman, René; Kalkhoven, Eric

2018-06-01

Nuclear receptors (NRs) are ligand-inducible transcription factors that play critical roles in metazoan development, reproduction, and physiology and therefore are implicated in a broad range of pathologies. The transcriptional activity of NRs critically depends on their interaction(s) with transcriptional coregulator proteins, including coactivators and corepressors. Short leucine-rich peptide motifs in these proteins (LxxLL in coactivators and LxxxIxxxL in corepressors) are essential and sufficient for NR binding. With 350 different coregulator proteins identified to date and with many coregulators containing multiple interaction motifs, an enormous combinatorial potential is present for selective NR-mediated gene regulation. However, NR-coregulator interactions have often been determined experimentally on a one-to-one basis across diverse experimental conditions. In addition, NR-coregulator interactions are difficult to predict because the molecular determinants that govern specificity are not well established. Therefore, many biologically and clinically relevant NR-coregulator interactions may remain to be discovered. Here, we present a comprehensive overview of 3696 NR-coregulator interactions by systematically characterizing the binding of 24 nuclear receptors with 154 coregulator peptides. We identified unique ligand-dependent NR-coregulator interaction profiles for each NR, confirming many well-established NR-coregulator interactions. Hierarchical clustering based on the NR-coregulator interaction profiles largely recapitulates the classification of NR subfamilies based on the primary amino acid sequences of the ligand-binding domains, indicating that amino acid sequence is an important, although not the only, molecular determinant in directing and fine-tuning NR-coregulator interactions. This NR-coregulator peptide interactome provides an open data resource for future biological and clinical discovery as well as NR-based drug design.

PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types

PubMed Central

BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL

2015-01-01

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541

Depression and family interaction among low-income, predominantly hispanic cancer patients: a longitudinal analysis.

PubMed

Oh, Hyunsung; Ell, Kathleen; Subica, Andrew

2014-02-01

Among cancer patients, family interaction has been associated with depression. According to the stress generation theory, depression among cancer patients triggers stressful interpersonal events that contribute to poor family interactions and additional depression. This conflict may occur with a spouse/partner or other family member, including extended family. This study evaluated the longitudinal association between depression and marital and family conflict among low-income, predominantly Hispanic cancer patients. Data were collected during a randomized controlled clinical trial of depression treatment among 472 low-income cancer patients with baseline depression scores of 10 or more on the Patient Health Questionnaire-9 and whose depression symptoms and negative family interactions were assessed at baseline and at 6, 12, 18, and 24 months. Considering that not all participants were in an intimate relationship, only 237 participants were included in the analysis of marital conflict. Mixed linear modeling with and without decomposition of between- and within-person variability was conducted to examine the longitudinal association between family interaction and depression. Overall, family conflict was significantly associated with changes in depression over time, and marital conflict was significantly associated with mean depression levels over 2 years. In addition, within-subject change in both marital and family conflict was significantly associated with within-patient deviation from average depression levels. Findings provide evidence of an association between depression and negative family interaction among depressed cancer patients. Cancer patients with clinically significant depressive symptoms may benefit from clinical assessment and psychotherapy relevant to family interaction.

'Bioengineered Bugs' - a patho-biotechnology approach to probiotic research and applications.

PubMed

Sleator, Roy D; Hill, Colin

2008-01-01

Given the increasing commercial and clinical relevance of probiotic cultures, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Pathogenic bacteria have evolved sophisticated strategies to overcome host defences, interact with the immune system and modulate essential host systems. The 'Patho-biotechnology' concept promotes the exploitation of these valuable traits for the design of more technologically robust and effective probiotic cultures with potentially improved biotechnological and clinical applications, as well as the development of novel vaccine and drug delivery platforms.

Adherence to drug-drug interaction alerts in high-risk patients: a trial of context-enhanced alerting.

PubMed

Duke, Jon D; Li, Xiaochun; Dexter, Paul

2013-05-01

Drug-drug interaction (DDI) alerting is an important form of clinical decision support, yet physicians often fail to attend to critical DDI warnings due to alert fatigue. We previously described a model for highlighting patients at high risk of a DDI by enhancing alerts with relevant laboratory data. We sought to evaluate the effect of this model on alert adherence in high-risk patients. A 6-month randomized controlled trial involving 1029 outpatient physicians was performed. The target interactions were all DDIs known to cause hyperkalemia. Alerts in the intervention group were enhanced with the patient's most recent potassium and creatinine levels. The control group received unmodified alerts. High -risk patients were those with baseline potassium >5.0 mEq/l and/or creatinine ≥1.5 mg/dl (132 μmol/l). We found no significant difference in alert adherence in high-risk patients between the intervention group (15.3%) and the control group (16.8%) (p=0.71). Adherence in normal risk patients was significantly lower in the intervention group (14.6%) than in the control group (18.6%) (p<0.01). In neither group did physicians increase adherence in patients at high risk. Physicians adhere poorly to hyperkalemia-associated DDI alerts even in patients with risk factors for a clinically significant interaction, and the display of relevant laboratory data in these alerts did not improve adherence levels in the outpatient setting. Further research is necessary to determine optimal strategies for conveying patient-specific DDI risk.

Potential drug-drug interactions with antiepileptic drugs in Medicaid recipients.

PubMed

Dickson, Michael; Bramley, Thomas J; Kozma, Chris; Doshi, Dilesh; Rupnow, Marcia F T

2008-09-15

The frequency of potential drug-drug interactions (DDIs) between antiepileptic drugs (AEDs) and other (non-AED) medications in Medicaid patients taking newer AED monotherapy, older AED monotherapy, and combinations of AED treatment was studied. A retrospective, observational study was conducted using administrative claims obtained from South Carolina Medicaid. Patients were included in the analysis if they (1) had at least one prescription for an AED between January 1, 2004, and December 31, 2004, (2) were taking a specific AED for at least 60 days, (3) had at least one epilepsy diagnosis during the 6 months before or during the enrollment period, and (4) were enrolled in Medicaid for at least 11 of the 12 months of the follow-up period. Possible DDI exposure was defined as 10 days of overlap between an AED and a non-AED known to have the potential to cause a clinically relevant interaction. A total of 4955 patients met the inclusion criteria. Approximately 45% of patients receiving monotherapy with an older AED had a potential DDI, compared with 3.9% receiving a newer AED. An average of 0.08 potential DDI per year of exposure occurred in the newer AED monotherapy cohort compared with 1.18 in the older AED monotherapy cohort. The most common potential interaction category was a decreased concentration of the non-AED. Older AEDs were associated with a greater likelihood of a potential DDI than were newer AEDs. Further research is needed to elucidate the relationship between the occurrence of potential DDIs and actual clinically relevant consequences.

Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation

PubMed Central

Gufford, Brandon T.; Chen, Gang; Lazarus, Philip; Graf, Tyler N.; Oberlies, Nicholas H.

2014-01-01

Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance–drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance–drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 determination. The IC50 values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC50 determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance–drug interactions that warrant advanced modeling and simulation to inform clinical assessment. PMID:25008344

Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs

PubMed Central

Rundfeldt, C; Gasparic, A; Wlaź, P

2014-01-01

Imepitoin is a novel anti-epileptic licensed in the European Union for the treatment of canine idiopathic epilepsy. The aim of this study was to characterize the pharmacokinetics of imepitoin in dogs and to evaluate the interaction with drug metabolizing enzymes. Upon administration of imepitoin tablets at a dose of 30 mg/kg to beagle dogs, high plasma levels were observed within 30 min following oral dosing, with maximal plasma concentrations of 14.9–17.2 μg/mL reached after 2–3 h. In a crossover study, co-administration of imepitoin tablets with food reduced the total AUC by 30%, but it did not result in significant changes in Tmax and Cmax, indicating lack of clinical relevance. No clinically relevant effects of sex and no accumulation or metabolic tolerance were observed upon twice daily dosing. Following single dose administration of 10–100 mg/kg, dose linearity was found. Administering [14C] imepitoin, high enteral absorption of 92% and primary fecal excretion were identified. Plasma protein binding was only 55%. At therapeutic plasma concentrations, imepitoin did not inhibit microsomal cytochrome P450 family liver enzymes in vitro. In rats, no relevant induction of liver enzymes was found. Therefore, protein binding or metabolism-derived drug–drug interactions are unlikely. Based on these data, imepitoin can be dosed twice daily, but the timing of tablet administration in relation to feeding should be kept consistent. PMID:24611573

Clinical relevance vs. statistical significance: Using neck outcomes in patients with temporomandibular disorders as an example.

PubMed

Armijo-Olivo, Susan; Warren, Sharon; Fuentes, Jorge; Magee, David J

2011-12-01

Statistical significance has been used extensively to evaluate the results of research studies. Nevertheless, it offers only limited information to clinicians. The assessment of clinical relevance can facilitate the interpretation of the research results into clinical practice. The objective of this study was to explore different methods to evaluate the clinical relevance of the results using a cross-sectional study as an example comparing different neck outcomes between subjects with temporomandibular disorders and healthy controls. Subjects were compared for head and cervical posture, maximal cervical muscle strength, endurance of the cervical flexor and extensor muscles, and electromyographic activity of the cervical flexor muscles during the CranioCervical Flexion Test (CCFT). The evaluation of clinical relevance of the results was performed based on the effect size (ES), minimal important difference (MID), and clinical judgement. The results of this study show that it is possible to have statistical significance without having clinical relevance, to have both statistical significance and clinical relevance, to have clinical relevance without having statistical significance, or to have neither statistical significance nor clinical relevance. The evaluation of clinical relevance in clinical research is crucial to simplify the transfer of knowledge from research into practice. Clinical researchers should present the clinical relevance of their results. Copyright © 2011 Elsevier Ltd. All rights reserved.

Interaction between shock coils increased the incidence of inappropriate therapies and lead failure in implantable cardioverter defibrillator.

PubMed

El Garhy, Mohammad; Ohlow, Marc-Alexander; Lauer, Bernward

Shock coil interaction in patients with multiple implantable cardioverter defibrillator (ICD) leads is occasionally observed. We aimed to evaluate the incidence of shock coil interaction and its clinical relevance. All ICD patients (646 patients) who came to follow up control in our ICD ambulance between January 1, 2011, and December 31, 2011 in the department of cardiology in Bad Berka hospital were retrospectively evaluated in this study. All baseline demographic, clinical, and procedural characteristics and postoperative chest x ray in postero-anterior and lateral view as well as clinical and ICD follow up data were evaluated. Among 646 patients 42 had multiple ICD leads (6.5%) of whom 36 patients (5.5% of total cohort patients and 85.7% of patients with multiple ICD leads) had shock coil interaction and presented the study group (Group I). The control group (Group II) consisted of 610 patients without coil-coil interaction including patients with single shock lead (604 patients) or patients with multiple leads but without interaction between shock coils (6 patients). Inappropriate anti-tachycardia therapies and RV lead revisions were more frequent in patients with interaction between shock coils (Group I vs Group II: 27.7% and 5.7%; p = 0.049 and 30.6% vs 6.4; p = 0.0001, respectively). Interaction between shock coils may be one of possible causes of lead failure and resulted in inappropriate therapies and subsequent lead revision. Copyright © 2018 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

PubMed

Kulmatycki, Kenneth; Hanna, Imad; Meyers, Dan; Salunke, Atish; Movva, Aishwarya; Majumdar, Tapan; Natrillo, Adrienne; Vapurcuyan, Arpine; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

2015-05-01

An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

Interactive cervical motion kinematics: sensitivity, specificity and clinically significant values for identifying kinematic impairments in patients with chronic neck pain.

PubMed

Sarig Bahat, Hilla; Chen, Xiaoqi; Reznik, David; Kodesh, Einat; Treleaven, Julia

2015-04-01

Chronic neck pain has been consistently shown to be associated with impaired kinematic control including reduced range, velocity and smoothness of cervical motion, that seem relevant to daily function as in quick neck motion in response to surrounding stimuli. The objectives of this study were: to compare interactive cervical kinematics in patients with neck pain and controls; to explore the new measures of cervical motion accuracy; and to find the sensitivity, specificity, and optimal cutoff values for defining impaired kinematics in those with neck pain. In this cross-section study, 33 patients with chronic neck pain and 22 asymptomatic controls were assessed for their cervical kinematic control using interactive virtual reality hardware and customized software utilizing a head mounted display with built-in head tracking. Outcome measures included peak and mean velocity, smoothness (represented by number of velocity peaks (NVP)), symmetry (represented by time to peak velocity percentage (TTPP)), and accuracy of cervical motion. Results demonstrated significant and strong effect-size differences in peak and mean velocities, NVP and TTPP in all directions excluding TTPP in left rotation, and good effect-size group differences in 5/8 accuracy measures. Regression results emphasized the high clinical value of neck motion velocity, with very high sensitivity and specificity (85%-100%), followed by motion smoothness, symmetry and accuracy. These finding suggest cervical kinematics should be evaluated clinically, and screened by the provided cut off values for identification of relevant impairments in those with neck pain. Such identification of presence or absence of kinematic impairments may direct treatment strategies and additional evaluation when needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

PubMed

Kosa, Rachel E; Lazzaro, Sarah; Bi, Yi-An; Tierney, Brendan; Gates, Dana; Modi, Sweta; Costales, Chester; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena V

2018-06-07

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors. Single dose rifampicin (30 mg/kg) significantly (p<0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin (AUC ratio ~21-39). Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (p<0.05) impacted the renal clearance of rosuvastatin (~8-fold). In vitro, rifampicin (10μM) inhibited uptake of pitavastatin, rosuvastatin and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP; while talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. The American Society for Pharmacology and Experimental Therapeutics.

Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial.

PubMed

Kochar, Ajar; Hellkamp, Anne S; Lokhnygina, Yuliya; Jones, W Schuyler; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Fox, Keith A A; Halperin, Jonathan L; Hankey, Graeme J; Mahaffey, Kenneth W; Nessel, Christopher C; Singer, Daniel E; Piccini, Jonathan P; Patel, Manesh R

2018-01-01

Atrial fibrillation (AF) increases risk of stroke 5-fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD. Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke. This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]). A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66-1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88-1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64). Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints. © 2018 Wiley Periodicals, Inc.

Biomolecular aspects of depression: A retrospective analysis.

PubMed

Peacock, Brandon N; Scheiderer, David J; Kellermann, Gottfried H

2017-02-01

The effects of psychological stress, oxidative stress, and chronic low grade inflammation on the neuro-immune connection have been implicated in the pathogenesis of depression. Thus, in the recent past, there has been a growing effort in determining the mechanism of this pathogenesis. While attempting to map out, this mechanism researchers and clinicians have searched for clinically relevant biomarkers for use in the diagnosis and for the assessment of those suffering from depression. In this study, we have performed a retrospective analysis of biomarkers with clinically relevant potentials, including peripheral catecholamines, chemokines, cytokines, and neurotransmitters. The retrospective analysis was performed on data collected over a six-year period of time (July 2009 to July 2015), gathered from patients (N=1399; Mage=42, SD=13; 71% female, 29% male) who submitted samples with complaints of feeling hopeless, worthless, isolated, alone, general sadness, overwhelmed, and/or a lack of interest in things they once enjoyed. The data collected consisted of quantitative values of urinary catecholamines and neurotransmitters (peripheral dopamine, epinephrine, histamine, kynurenic acid, norepinephrine, β-PEA, and serotonin), salivary hormones (peripheral cortisol and melatonin), and peripheral blood mononuclear cell secreted cytokines and chemokines (Interleukins 1β, 6, 8, 10, MCP-1, GCSF, and TNFα). Statistical and clinical significance was assessed by comparison with a control group (N=2395; Mage=42, SD=13; 70% female, 30% male), calculating the percent mean difference, p value, and effect size (Cohen's ɗ) for each parameter between groups. The findings of this study suggested that, in a model of general depression, there is a dysregulation in the enzymatic production and degradation of catecholamines, neurotransmitters, hormones, and immunological proteins. A cycle of interaction was found between all of these biomolecules, where an increase or decrease in one marker could result in a stimulatory or inhibitory effect on others. The mechanism of this was proposed to occur through the interaction of psychological stress, inflammation, and oxidative stress pathways. All of these biomolecules were found to be significantly altered in the general depression group and are key components of the interaction between the neurological and immunological systems. This study serves to further elucidate the role of biomolecules in the regulation of affective disorders, such as depression. Resulting in providing a network of clinically relevant biomarkers to objectively assess and monitor general depression. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Budding off: bringing functional genomics to Candida albicans.

PubMed

Anderson, Matthew Z; Bennett, Richard J

2016-03-01

Candida species are the most prevalent human fungal pathogens, with Candida albicans being the most clinically relevant species. Candida albicans resides as a commensal of the human gastrointestinal tract but is a frequent cause of opportunistic mucosal and systemic infections. Investigation of C. albicans virulence has traditionally relied on candidate gene approaches, but recent advances in functional genomics have now facilitated global, unbiased studies of gene function. Such studies include comparative genomics (both between and within Candida species), analysis of total RNA expression, and regulation and delineation of protein-DNA interactions. Additionally, large collections of mutant strains have begun to aid systematic screening of clinically relevant phenotypes. Here, we will highlight the development of functional genomics in C. albicans and discuss the use of these approaches to addressing both commensalism and pathogenesis in this species. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Self-medication for cough and the common cold: information needs of consumers.

PubMed

Kloosterboer, Sanne Maartje; McGuire, Treasure; Deckx, Laura; Moses, Geraldine; Verheij, Theo; van Driel, Mieke L

2015-07-01

Despite the high use of over-the-counter (OTC) cough and cold medicines, little is known about Australia's cough and cold medicines information needs. The aim of this study was to identify gaps in consumers' perceived knowledge and concerns, to better target consumer medicines information and improve quality use of medicines. We analysed cough-and-cold related enquiries from consumers who contacted an Australian national medicine call centre between September 2002 and June 2010. Of 5503 cough and cold calls, female callers made up 86% of the calls and 33% were related to children. Questions most frequently related to drug-drug interactions (29%). An analysis of narratives over an 18-month period (248 calls) revealed 20% of the calls concerned potentially clinically relevant interactions, particularly those involving psychotropic agents. The potential for interactions with cough and cold medicines purchased OTC is recognised by consumers. Patient information should address their concerns. Doctors should be aware of the common cough and cold interactions and communicate likely clinical symptoms to patients when prescribing medication to prevent potential harm.

Clinical Aspects of Idiopathic Inflammatory Bowel Disease: A Review for Pathologists.

PubMed

Lee, Hwajeong; Westerhoff, Maria; Shen, Bo; Liu, Xiuli

2016-05-01

-Idiopathic inflammatory bowel disease manifests with different clinical phenotypes showing varying behavior and risk for neoplasia. The clinical questions that are posed to pathologists differ depending on phase of the disease and the clinical circumstances. Understanding the clinical aspects of the dynamic disease process will enhance the role of pathology in optimizing the care of patients with inflammatory bowel disease. -To review clinical and surgical aspects of inflammatory bowel disease that are relevant to practicing pathologists. -The literature was reviewed. -Diagnosis and management of inflammatory bowel disease require an integrated evaluation of clinical, endoscopic, radiologic, and pathologic features. Therefore, close interaction between clinicians and pathologists is crucial. Having this team approach improves understanding of the pertinent clinical and surgical aspects of the disease and assists in the recognition of unusual presentation of variants, as well as mimics of idiopathic inflammatory bowel disease, by pathologists.

A hierarchy of effective teaching and learning to acquire competence in evidenced-based medicine

PubMed Central

Khan, Khalid S; Coomarasamy, Arri

2006-01-01

Background A variety of methods exists for teaching and learning evidence-based medicine (EBM). However, there is much debate about the effectiveness of various EBM teaching and learning activities, resulting in a lack of consensus as to what methods constitute the best educational practice. There is a need for a clear hierarchy of educational activities to effectively impart and acquire competence in EBM skills. This paper develops such a hierarchy based on current empirical and theoretical evidence. Discussion EBM requires that health care decisions be based on the best available valid and relevant evidence. To achieve this, teachers delivering EBM curricula need to inculcate amongst learners the skills to gain, assess, apply, integrate and communicate new knowledge in clinical decision-making. Empirical and theoretical evidence suggests that there is a hierarchy of teaching and learning activities in terms of their educational effectiveness: Level 1, interactive and clinically integrated activities; Level 2(a), interactive but classroom based activities; Level 2(b), didactic but clinically integrated activities; and Level 3, didactic, classroom or standalone teaching. Summary All health care professionals need to understand and implement the principles of EBM to improve care of their patients. Interactive and clinically integrated teaching and learning activities provide the basis for the best educational practice in this field. PMID:17173690

Susceptibility based upon Chemical Interaction with Disease ...

EPA Pesticide Factsheets

One of the challenges facing toxicology and risk assessment is that numerous host and environmental factors may modulate vulnerability and risk. An area of increasing interest is the potential for chemicals to interact with background aging and disease processes, an interaction that may yield cumulative damage, altered chemical potency, and increased disease incidence. This review outlines the interactions possible between chemicals and background disease and identifies the type of information needed to evaluate such interactions. Key among these is the existence of a clinically relevant and easy to measure biomarker of disease risk which allows the identification of vulnerable individuals based upon the level of risk biomarker. The impact of toxic chemicals on this biomarker can then be used to predict how the chemical modifies disease risk as long as related mechanistic and toxicological data are consistent with toxicant effect on the disease process. Several case studies are briefly presented which describe the toxic chemical, the clinical biomarker and the impacted disease including: fine particulate matter/decreased heart rate variability/increased cardiopulmonary events; cadmium/decreased glomerular filtration rate/increased chronic kidney disease; methyl mercury/decreased paraoxonase-1/increased cardiovascular risk; trichloroethylene/increased anti-nuclear antibody/autoimmunity; dioxin/increased CYP1A1/hypertension. These case studies point o

Bidirectional interactions between indomethacin and the murine intestinal microbiota

PubMed Central

Liang, Xue; Bittinger, Kyle; Li, Xuanwen; Abernethy, Darrell R; Bushman, Frederic D; FitzGerald, Garret A

2015-01-01

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is probably the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin — thus, the drug-microbe interactions described here provide candidate mediators of individualized drug responses. DOI: http://dx.doi.org/10.7554/eLife.08973.001 PMID:26701907

Hunter disease eClinic: interactive, computer-assisted, problem-based approach to independent learning about a rare genetic disease.

PubMed

Al-Jasmi, Fatma; Moldovan, Laura; Clarke, Joe T R

2010-10-25

Computer-based teaching (CBT) is a well-known educational device, but it has never been applied systematically to the teaching of a complex, rare, genetic disease, such as Hunter disease (MPS II). To develop interactive teaching software functioning as a virtual clinic for the management of MPS II. The Hunter disease eClinic, a self-training, user-friendly educational software program, available at the Lysosomal Storage Research Group (http://www.lysosomalstorageresearch.ca), was developed using the Adobe Flash multimedia platform. It was designed to function both to provide a realistic, interactive virtual clinic and instantaneous access to supporting literature on Hunter disease. The Hunter disease eClinic consists of an eBook and an eClinic. The eClinic is the interactive virtual clinic component of the software. Within an environment resembling a real clinic, the trainee is instructed to perform a medical history, to examine the patient, and to order appropriate investigation. The program provides clinical data derived from the management of actual patients with Hunter disease. The eBook provides instantaneous, electronic access to a vast collection of reference information to provide detailed background clinical and basic science, including relevant biochemistry, physiology, and genetics. In the eClinic, the trainee is presented with quizzes designed to provide immediate feedback on both trainee effectiveness and efficiency. User feedback on the merits of the program was collected at several seminars and formal clinical rounds at several medical centres, primarily in Canada. In addition, online usage statistics were documented for a 2-year period. Feedback was consistently positive and confirmed the practical benefit of the program. The online English-language version is accessed daily by users from all over the world; a Japanese translation of the program is also available. The Hunter disease eClinic employs a CBT model providing the trainee with realistic clinical problems, coupled with comprehensive basic and clinical reference information by instantaneous access to an electronic textbook, the eBook. The program was rated highly by attendees at national and international presentations. It provides a potential model for use as an educational approach to other rare genetic diseases.

Comparison of gesture and conventional interaction techniques for interventional neuroradiology.

PubMed

Hettig, Julian; Saalfeld, Patrick; Luz, Maria; Becker, Mathias; Skalej, Martin; Hansen, Christian

2017-09-01

Interaction with radiological image data and volume renderings within a sterile environment is a challenging task. Clinically established methods such as joystick control and task delegation can be time-consuming and error-prone and interrupt the workflow. New touchless input modalities may have the potential to overcome these limitations, but their value compared to established methods is unclear. We present a comparative evaluation to analyze the value of two gesture input modalities (Myo Gesture Control Armband and Leap Motion Controller) versus two clinically established methods (task delegation and joystick control). A user study was conducted with ten experienced radiologists by simulating a diagnostic neuroradiological vascular treatment with two frequently used interaction tasks in an experimental operating room. The input modalities were assessed using task completion time, perceived task difficulty, and subjective workload. Overall, the clinically established method of task delegation performed best under the study conditions. In general, gesture control failed to exceed the clinical input approach. However, the Myo Gesture Control Armband showed a potential for simple image selection task. Novel input modalities have the potential to take over single tasks more efficiently than clinically established methods. The results of our user study show the relevance of task characteristics such as task complexity on performance with specific input modalities. Accordingly, future work should consider task characteristics to provide a useful gesture interface for a specific use case instead of an all-in-one solution.

Effects of stress and mental toughness on burnout and depressive symptoms: A prospective study with young elite athletes.

PubMed

Gerber, Markus; Best, Simon; Meerstetter, Fabienne; Walter, Marco; Ludyga, Sebastian; Brand, Serge; Bianchi, Renzo; Madigan, Daniel J; Isoard-Gautheur, Sandrine; Gustafsson, Henrik

2018-05-18

To examine in a sample of young elite athletes (a) the presence of clinically relevant symptoms of burnout and depression, and (b) a possible interaction of perceived stress and mental toughness in the prediction of burnout and depressive symptoms. 6-month prospective study. A representative sample of 257 young elite athletes (M=16.82years, SD=1.44, 36% females) was recruited in North-Western Switzerland. 197 athletes were followed-up across a 6-month period. Burnout was assessed with the Shirom-Melamed Burnout Measure (SMBM), and depression with the 9-item depression module of the Patient Health Questionnaire (PHQ). Values of ≥4.40 (SMBM) and >14 (PHQ-9) were considered indicative of clinically relevant burnout or depression. Stress perceptions were assessed with the Perceived Stress Scale (PSS), and mental toughness with the Mental Toughness Questionnaire (MTQ). Hierarchical regression analyses were used to test stress-buffering effects. The percentage of athletes with clinically relevant levels of burnout and depressive symptoms was 12% and 9%, respectively. Both cross-sectional and prospective analyses showed that compared to participants with low mental toughness, those with higher mental toughness scores reported significantly fewer mental health issues, when exposed to high stress. By contrast, when stress levels were low, mental toughness was unrelated to psychological health complaints. About every tenth young elite athlete reported burnout or depressive symptoms of potential clinical relevance. While high perceived stress was associated with increased psychological health complaints, mental toughness was able to off-set some of the negative consequences resulting from high stress exposure. Copyright © 2018 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

A European multi-language initiative to make the general population aware of independent clinical research: the European Communication on Research Awareness Need project.

PubMed

Mosconi, Paola; Antes, Gerd; Barbareschi, Giorgio; Burls, Amanda; Demotes-Mainard, Jacques; Chalmers, Iain; Colombo, Cinzia; Garattini, Silvio; Gluud, Christian; Gyte, Gill; Mcllwain, Catherine; Penfold, Matt; Post, Nils; Satolli, Roberto; Valetto, Maria Rosa; West, Brian; Wolff, Stephanie

2016-01-12

The ECRAN (European Communication on Research Awareness Needs) project was initiated in 2012, with support from the European Commission, to improve public knowledge about the importance of independent, multinational, clinical trials in Europe. Participants in the ECRAN consortium included clinicians and methodologists directly involved in clinical trials; researchers working in partnership with the public and patients; representatives of patients; and experts in science communication. We searched for, and evaluated, relevant existing materials and developed additional materials and tools, making them freely available under a Creative Commons licence. The principal communication materials developed were: 1. A website ( http://ecranproject.eu ) in six languages, including a Media centre section to help journalists to disseminate information about the ECRAN project 2. An animated film about clinical trials, dubbed in the 23 official languages of the European Community, and an interactive tutorial 3. An inventory of resources, available in 23 languages, searchable by topic, author, and media type 4. Two educational games for young people, developed in six languages 5. Testing Treatments interactive in a dozen languages, including five official European Community languages 6. An interactive tutorial slide presentation testing viewers' knowledge about clinical trials Over a 2-year project, our multidisciplinary and multinational consortium was able to produce, and make freely available in many languages, new materials to promote public knowledge about the importance of independent and international clinical trials. Sustained funding for the ECRAN information platform could help to promote successful recruitment to independent clinical trials supported through the European Clinical Research Infrastructure Network.

Calcium channel blockers: spectrum of side effects and drug interactions.

PubMed

Hedner, T

1986-01-01

Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of beta-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.

Effects of short-term addition of NSAID to diuretics and/or RAAS-inhibitors on blood pressure and renal function.

PubMed

Nygård, Peder; Jansman, Frank G A; Kruik-Kollöffel, Willemien J; Barnaart, Alex F W; Brouwers, Jacobus R B J

2012-06-01

The combined post-operative use of diuretics and/or renin-angiotensin-aldosterone system (RAAS) inhibitors may increase the risk of nonsteroidal anti-inflammatory drug (NSAID) associated renal failure because of a drug-drug interaction. The aim of this study was to investigate the effect of the short-term (<4 days) post-operative combined use of NSAIDs with diuretics and/or RAAS inhibitors on renal function and blood pressure. One teaching hospital in the Netherlands. The study-design was a prospective, observational cohort-study. Based on postoperative treatment with NSAIDs, the intervention-group was compared to a control-group (no NSAIDs treatment). Systolic blood pressure and renal function expressed by the estimated glomular filtration rate (eGFR) calculated with the modification of renal desease formula. 97 patients were included in the intervention-group, 53 patients in the control-group. Patient characteristics were comparable except for one variable: 'combined use of a diuretic with a RAAS inhibitor' which was higher in the control-group (62 vs. 43 %, p = 0.046). Odds ratio for clinically relevant increase in systolic blood pressure was 0.66 (CI95 % 0.3-1.5). Odds ratio for clinical relevant decrease in renal function was 2.44 (CI95 % 1.1-5.2). On day 4 eGFR of 3 patients in the intervention- and 1 in the control-group was <50 ml/min/1.73 m(2). Odds ratios showed no significant difference of a clinically relevant increase in systolic blood pressure but showed a higher risk for a clinically relevant decrease in renal function in the intervention group. However this decrease resulted in a relevant impaired renal function (<50 ml/min/1.73 m(2)) in only 3 patients in the interventiongroup and 1 patient in the control-group. In the post-operative patient, without preexisting impaired renal function, concurrent diuretics and/or renin-angiotensinaldosterone system inhibitor therapy can be combined with short-term NSAID treatment.

Recent advances in liquid-phase separations for clinical metabolomics.

PubMed

Kohler, Isabelle; Giera, Martin

2017-01-01

Over the last decades, several technological improvements have been achieved in liquid-based separation techniques, notably, with the advent of fully porous sub-2 μm particles and superficially porous sub-3 μm particles, the comeback of supercritical fluid chromatography, and the development of alternative chromatographic modes such as hydrophilic interaction chromatography. Combined with mass spectrometry, these techniques have demonstrated their added value, substantially increasing separation efficiency, selectivity, and speed of analysis. These benefits are essential in modern clinical metabolomics typically involving the study of large-scale sample cohorts and the analysis of thousands of metabolites showing extensive differences in physicochemical properties. This review presents a brief overview of the recent developments in liquid-phase separation sciences in the context of clinical metabolomics, focusing on increased throughput as well as metabolite coverage. Relevant metabolomics applications highlighting the benefits of ultra-high performance liquid chromatography, core-shell technology, high-temperature liquid chromatography, capillary electrophoresis, supercritical fluid chromatography, and hydrophilic interaction chromatography are discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The default network and self-generated thought: component processes, dynamic control, and clinical relevance

PubMed Central

Andrews-Hanna, Jessica R.; Smallwood, Jonathan; Spreng, R. Nathan

2014-01-01

Though only a decade has elapsed since the default network was first emphasized as being a large-scale brain system, recent years have brought great insight into the network’s adaptive functions. A growing theme highlights the default network as playing a key role in internally-directed—or self-generated—thought. Here, we synthesize recent findings from cognitive science, neuroscience, and clinical psychology to focus attention on two emerging topics as current and future directions surrounding the default network. First, we present evidence that self-generated thought is a multi-faceted construct whose component processes are supported by different subsystems within the network. Second, we highlight the dynamic nature of the default network, emphasizing its interaction with executive control systems when regulating aspects of internal thought. We conclude by discussing clinical implications of disruptions to the integrity of the network, and consider disorders when thought content becomes polarized or network interactions become disrupted or imbalanced. PMID:24502540

Social Support Moderates the Relationship between Sleep and Inflammation in a Population at High Risk for Developing Cardiovascular Disease

PubMed Central

Tomfohr, Lianne M.; Edwards, Kate M.; Madsen, Joshua W.; Mills, Paul J.

2015-01-01

Poor sleep and low social support have each been associated with mortality and morbidity from chronic illness and a small body of research suggests that the two interact to influence systemic inflammation, whereby good social relationships may buffer the relationship between poor sleep and increased inflammation. The current study investigated interactions between sleep and social support in the prediction of inflammation in a clinical population (prehypertensive and hypertensive individuals) at high risk for the development of cardiovascular disease. Using a standardized subjective measure of sleep quality, we found that social support moderated the association between sleep and circulating levels of both IL-6 and CRP, such that poor sleep appeared to confer a risk of increased inflammation only in those participants who also reported low social support. In women, the same relationship was observed for TNF-α. These results extend previous findings into a clinical population and also demonstrate that sleep quality and social support interact in the prediction of two previously uninvestigated clinically relevant inflammatory markers (CRP and TNF-α). High levels of perceived social support may compensate for the negative health impact of poor sleep quality and vice versa. PMID:26402487

Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.

PubMed

Zhai, S; Georgy, A; Liang, Z; Zhi, J

2016-11-01

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability. © 2016, The American College of Clinical Pharmacology.

Children's rights in pediatrics.

PubMed

Streuli, Jürg C; Michel, Margot; Vayena, Effy

2011-01-01

The United Nations Convention of Children's Rights (UNCRC) introduced in 1989 has generated a global movement for the protection of children's rights and has brought about a paradigm change in how children are perceived. Pediatric healthcare professionals are interacting with children and therefore with children's rights on a daily basis. However, although at least 18 of the 54 articles are relevant for pediatric practice, there is limited systematic training on how pediatricians can support children's rights in the clinical setting. This article discusses the principles and aims of the UNCRC and proposes a comprehensive checklist of rights vis-à-vis issues that arise in clinical practice.

Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.

PubMed

Macha, Sreeraj; Sennewald, Regina; Rose, Peter; Schoene, Katja; Pinnetti, Sabine; Woerle, Hans J; Broedl, Uli C

2013-03-01

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril). Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

PubMed

Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

2016-08-01

Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma

PubMed Central

Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G.; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

2016-01-01

Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

Ablation of clinically relevant kidney tissue volumes by high-intensity focused ultrasound: Preliminary results of standardized ex-vivo investigations.

PubMed

Häcker, Axel; Peters, Kristina; Knoll, Thomas; Marlinghaus, Ernst; Alken, Peter; Jenne, Jürgen W; Michel, Maurice Stephan

2006-11-01

To investigate strategies to achieve confluent kidney-tissue ablation by high-intensity focused ultrasound (HIFU). Our model of the perfused ex-vivo porcine kidney was used. Tissue ablation was performed with an experimental HIFU device (Storz Medical, Kreuzlingen, Switzerland). Lesion-to-lesion interaction was investigated by varying the lesion distance (5 to 2.5 mm), generator power (300, 280, and 260 W), cooling time (10, 20, and 30 seconds), and exposure time (4, 3, and 2 seconds). The lesion rows were analyzed grossly and by histologic examination (hematoxylin-eosin and nicotinamide adenine dinucleotide staining). It was possible to achieve complete homogeneous ablation of a clinically relevant tissue volume but only by meticulous adjustment of the exposure parameters. Minimal changes in these parameters caused changes in lesion formation with holes within the lesions and lesion-to-lesion interaction. Our preliminary results show that when using this new device, HIFU can ablate a large tissue volume homogeneously in perfused ex-vivo porcine tissue under standardized conditions with meticulous adjustment of exposure parameters. Further investigations in vivo are necessary to test whether large tissue volumes can be ablated completely and reliably despite the influence of physiologic tissue and organ movement.

Bioassays Based on Molecular Nanomechanics

DOE PAGES

Majumdar, Arun

2002-01-01

Recent experiments have shown that when specific biomolecular interactions are confined to one surface of a microcantilever beam, changes in intermolecular nanomechanical forces provide sufficient differential torque to bend the cantilever beam. This has been used to detect single base pair mismatches during DNA hybridization, as well as prostate specific antigen (PSA) at concentrations and conditions that are clinically relevant for prostate cancer diagnosis. Since cantilever motion originates from free energy change induced by specific biomolecular binding, this technique is now offering a common platform for label-free quantitative analysis of protein-protein binding, DNA hybridization DNA-protein interactions, and in general receptor-ligandmore » interactions. Current work is focused on developing “universal microarrays” of microcantilever beams for high-throughput multiplexed bioassays.« less

Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs.

PubMed

Rundfeldt, C; Gasparic, A; Wlaź, P

2014-10-01

Imepitoin is a novel anti-epileptic licensed in the European Union for the treatment of canine idiopathic epilepsy. The aim of this study was to characterize the pharmacokinetics of imepitoin in dogs and to evaluate the interaction with drug metabolizing enzymes. Upon administration of imepitoin tablets at a dose of 30 mg/kg to beagle dogs, high plasma levels were observed within 30 min following oral dosing, with maximal plasma concentrations of 14.9-17.2 μg/mL reached after 2-3 h. In a crossover study, co-administration of imepitoin tablets with food reduced the total AUC by 30%, but it did not result in significant changes in Tmax and Cmax , indicating lack of clinical relevance. No clinically relevant effects of sex and no accumulation or metabolic tolerance were observed upon twice daily dosing. Following single dose administration of 10-100 mg/kg, dose linearity was found. Administering [(14) C] imepitoin, high enteral absorption of 92% and primary fecal excretion were identified. Plasma protein binding was only 55%. At therapeutic plasma concentrations, imepitoin did not inhibit microsomal cytochrome P450 family liver enzymes in vitro. In rats, no relevant induction of liver enzymes was found. Therefore, protein binding or metabolism-derived drug-drug interactions are unlikely. Based on these data, imepitoin can be dosed twice daily, but the timing of tablet administration in relation to feeding should be kept consistent. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Clinical analysis of genome next-generation sequencing data using the Omicia platform

PubMed Central

Coonrod, Emily M; Margraf, Rebecca L; Russell, Archie; Voelkerding, Karl V; Reese, Martin G

2013-01-01

Aims Next-generation sequencing is being implemented in the clinical laboratory environment for the purposes of candidate causal variant discovery in patients affected with a variety of genetic disorders. The successful implementation of this technology for diagnosing genetic disorders requires a rapid, user-friendly method to annotate variants and generate short lists of clinically relevant variants of interest. This report describes Omicia’s Opal platform, a new software tool designed for variant discovery and interpretation in a clinical laboratory environment. The software allows clinical scientists to process, analyze, interpret and report on personal genome files. Materials & Methods To demonstrate the software, the authors describe the interactive use of the system for the rapid discovery of disease-causing variants using three cases. Results & Conclusion Here, the authors show the features of the Opal system and their use in uncovering variants of clinical significance. PMID:23895124

In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions

PubMed Central

Bartizal, K.; Minassian, S. L.; Fang, E.; Prokocimer, P.

2013-01-01

Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS). PMID:23612197

In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions.

PubMed

Flanagan, S; Bartizal, K; Minassian, S L; Fang, E; Prokocimer, P

2013-07-01

Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥ 30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥ 2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS).

Beyond misdiagnosis, misunderstanding and mistrust: relevance of the historical perspective in the medical and mental health treatment of people of color.

PubMed Central

Suite, Derek H.; La Bril, Robert; Primm, Annelle; Harrison-Ross, Phyllis

2007-01-01

In this article, we discuss the relationship and relevance of the historical interaction primarily between African-American culture and the medical and mental health communities, and explore the role of historical experience in contributing to mistrust and underutilization of services by people of color. We conclude that failure on the part of practitioners to go beyond clinical history gathering to recognize and acknowledge the larger historical perspectives from which they and their patients of color draw conclusions and make decisions contributes to the mistrust of the medical and mental health communities and to perpetuation of the current climate of healthcare disparities. PMID:17722664

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

PubMed

Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

2017-05-01

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin C max by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CL int,T ) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves C max that coincide with the low C max of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase. Copyright © 2017. Published by Elsevier Inc.

Antiepileptic treatment in paediatric oncology--an interdisciplinary challenge.

PubMed

Tibussek, D; Distelmaier, F; Schönberger, S; Göbel, U; Mayatepek, E

2006-01-01

Epileptic seizures are a common and clinically relevant problem in paediatric oncology. Attributable to the heterogeneity of this group of patients and a number of possible comorbidities antiepileptic treatment in paediatric oncology poses a number of diagnostic and therapeutic challenges. This requires a close interdisciplinary approach to the seizing child or adolescent. A prompt and detailed diagnostic work-up is needed in every case in order to establish the diagnosis and, equally important, to detect secondary aetiological factors, e. g. epileptogenic drugs or any acute underlying pathology, such as metabolic or toxic encephalopathies, CNS-infections or cerebrovascular events. This might offer the opportunity for a specific causative treatment and thus prevent unnecessary long-term antiepileptic drug (AED) treatment. If AED treatment is initiated several aspects have to be taken into account. Most importantly, AEDs and chemotherapeutic drugs (CTDs) may interact. Depending on the comedication this may result in reduced tumour or seizure control or unexpected toxicity of AEDs or CTDs. Understanding these interactions will allow to anticipate clinically relevant adverse effects. AED may be further complicated by side-effects, some of them of particular concern for children or adolescents, such as cognitive effects, myelotoxicity, serious rashes, endocrinological disturbances, and many more. Beside critically questioning the need for AED treatment it is therefore important to prefer AED with a good safety-profile in this population. Enzyme-inducing and inhibiting AED should be avoided if possible. Preliminary studies indicate that gabapentin and levetiracetam may provide good options in terms of efficacy and safety. However, more properly designed clinical studies are warranted to raise the level of evidence for robust clinical recommendations. Until that time, clinicians will need to continue to question current policies and adapt their daily practice to evolving scientific data.

Pharmacogenetically driven treatments for alcoholism: are we there yet?

PubMed

Arias, Albert J; Sewell, R Andrew

2012-06-01

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.

Clinical relevance in anesthesia journals.

PubMed

Lauritsen, Jakob; Møller, Ann M

2006-04-01

The purpose of this review is to present the latest knowledge and research on the definition and distribution of clinically relevant articles in anesthesia journals. It will also discuss the importance of the chosen methodology and outcome of articles. In the last few years, more attention has been paid to evidence-based medicine in anesthesia. Several articles on the subject have focused on the need to base clinical decisions on sound research employing both methodological rigor and clinically relevant outcomes. The number of systematic reviews in anesthesia literature is increasing as well as the focus on diminishing the number of surrogate outcomes. It has been shown that the impact factor is not a valid measure of establishing the level of clinical relevance to a journal. This review presents definitions of clinically relevant anesthesia articles. A clinically relevant article employs both methodological rigor and a clinically relevant outcome. The terms methodological rigor and clinical outcomes are fully discussed in the review as well as problems with journal impact factors.

Interactive computer-assisted instruction in acid-base physiology for mobile computer platforms.

PubMed

Longmuir, Kenneth J

2014-03-01

In this project, the traditional lecture hall presentation of acid-base physiology in the first-year medical school curriculum was replaced by interactive, computer-assisted instruction designed primarily for the iPad and other mobile computer platforms. Three learning modules were developed, each with ∼20 screens of information, on the subjects of the CO2-bicarbonate buffer system, other body buffer systems, and acid-base disorders. Five clinical case modules were also developed. For the learning modules, the interactive, active learning activities were primarily step-by-step learner control of explanations of complex physiological concepts, usually presented graphically. For the clinical cases, the active learning activities were primarily question-and-answer exercises that related clinical findings to the relevant basic science concepts. The student response was remarkably positive, with the interactive, active learning aspect of the instruction cited as the most important feature. Also, students cited the self-paced instruction, extensive use of interactive graphics, and side-by-side presentation of text and graphics as positive features. Most students reported that it took less time to study the subject matter with this online instruction compared with subject matter presented in the lecture hall. However, the approach to learning was highly examination driven, with most students delaying the study of the subject matter until a few days before the scheduled examination. Wider implementation of active learning computer-assisted instruction will require that instructors present subject matter interactively, that students fully embrace the responsibilities of independent learning, and that institutional administrations measure instructional effort by criteria other than scheduled hours of instruction.

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse

PubMed Central

Jacobsen, Jacob P.R.; Plenge, Per; Sachs, Benjamin D.; Pehrson, Alan L.; Cajina, Manuel; Du, Yunzhi; Roberts, Wendy; Rudder, Meghan L.; Dalvi, Prachiti; Robinson, Taylor J.; O’Neill, Sharon P.; Khoo, King S.; Morillo, Connie Sanchez; Zhang, Xiaodong; Caron, Marc G.

2015-01-01

Rationale Escitalopram is a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram’s inhibition hereof. Objectives Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Methods Recombinant technology; in vivo microdialysis; receptor binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). Results We generated mice expressing either the wild-type human SERT (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/VFL+SI/TT). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. Importantly, escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment. Further, escitalopram-induced 5-HTExt elevation was not affected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small, tending to be enhanced by R-citalopram co-administration. Conclusions We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram. Our findings points to mechanisms for R-citalopram antagonism of escitalopram’s antidepressant action other than direct antagonistic binding interactions at the hSERT. PMID:24810106

Attachment and Chronic Pain in Children and Adolescents

PubMed Central

Donnelly, Theresa J.; Jaaniste, Tiina

2016-01-01

Although attachment theory is not new, its theoretical implications for the pediatric chronic pain context have not been thoroughly considered, and the empirical implications and potential clinical applications are worth exploring. The attachment framework broadly focuses on interactions between a child’s developing self-regulatory systems and their caregiver’s responses. These interactions are believed to create a template for how individuals will relate to others in the future, and may help account for normative and pathological patterns of emotions and behavior throughout life. This review outlines relevant aspects of the attachment framework to the pediatric chronic pain context. The theoretical and empirical literature is reviewed regarding the potential role of attachment-based constructs such as vulnerability and maintaining factors of pediatric chronic pain. The nature and targets of attachment-based pediatric interventions are considered, with particular focus on relevance for the pediatric chronic pain context. The potential role of attachment style in the transition from acute to chronic pain is considered, with further research directions outlined. PMID:27792141

The relevance of security: A latent domain of attachment relationships.

PubMed

Mannarini, Stefania; Boffo, Marilisa

2014-02-01

In the present study an adult attachment dimension, latent to the constructs of security, anxiety, and avoidance, was hypothesized, wherein security was expected to occupy the most relevant position. Furthermore, the reciprocal functioning of attachment constructs and their interactions with self-esteem were explored. Four hundreds and thirty-four Italian university students responded to two adult attachment questionnaires (Attachment Style Questionnaire and Adult Attachment Questionnaire) and to the Rosenberg Self-esteem scale. A Many-Facet Rasch Measurement modeling approach was adopted. The main results can be summarized as follows: (a) security, anxiety, and avoidance are nested under one latent attachment dimension; (b) security occupies the most prominent position on the dimension; (c) security is positively associated with a moderate level of attachment anxiety and negatively related to avoidance; and (d) a positive interaction between self-esteem and security, and a negative relation between self-esteem and anxiety, were detected. Theoretical, clinical, and empirical implications of the results are further discussed. © 2013 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

TARGETING POLYMER THERAPEUTICS TO BONE

PubMed Central

Low, Stewart; Kopeček, Jindřich

2012-01-01

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody

PubMed Central

Norman, Andrew B; Ball, William J

2012-01-01

The effects of a humanized monoclonal antibody (mAb) having high affinity and specificity for cocaine in animal models are reviewed. The mAb reduced the concentration of cocaine in the brain of mice after intravenous injection of cocaine. In addition, the mAb increased the concentration of cocaine required to reinstate cocaine self-administration. These effects may predict clinical efficacy of a passive immunotherapy for reducing the probability of cocaine-induced relapse. However, in the presence of the mAb, once cocaine self-administration was reinstated, the consumption rate of cocaine was increased. This effect is hypothesized to result from a pharmacokinetic/pharmacodynamic interaction. A humanized mAb should minimize adverse events related to the immunogenicity of the mAb protein, and the specificity for cocaine should avoid adverse events related to interactions with physiologically relevant endogenous proteins. PMID:22401638

A Knowledge-Based System for the Computer Assisted Diagnosis of Endoscopic Images

NASA Astrophysics Data System (ADS)

Kage, Andreas; Münzenmayer, Christian; Wittenberg, Thomas

Due to the actual demographic development the use of Computer-Assisted Diagnosis (CAD) systems becomes a more important part of clinical workflows and clinical decision making. Because changes on the mucosa of the esophagus can indicate the first stage of cancerous developments, there is a large interest to detect and correctly diagnose any such lesion. We present a knowledge-based system which is able to support a physician with the interpretation and diagnosis of endoscopic images of the esophagus. Our system is designed to support the physician directly during the examination of the patient, thus prodving diagnostic assistence at the point of care (POC). Based on an interactively marked region in an endoscopic image of interest, the system provides a diagnostic suggestion, based on an annotated reference image database. Furthermore, using relevant feedback mechanisms, the results can be enhanced interactively.

An Interactive Ambulatory Nephrology Curriculum for Internal Medicine Interns: Design, Implementation, and Participant Feedback.

PubMed

Gomez, Alexis C; Warburton, Karen M; Miller, Rachel K; Negoianu, Dan; Cohen, Jordana B

2017-09-01

While diminishing nephrology fellow recruitment is a known issue, more work is needed to evaluate possible interventions to reverse this trend. We designed and implemented a curriculum to increase exposure to ambulatory nephrology among internal medicine interns. The curriculum focused on key aspects of outpatient nephrology practice, including supervised clinic visits, formal themed didactic content, and an online interactive forum with assigned evidence-based readings and small-group responses to relevant cases. We obtained postcourse surveys from all participating interns. Of the 43 interns who took part in the first year of the ambulatory nephrology curriculum, 100% reported a positive didactic experience and 91% reported a positive interactive online experience. 77% reported an improvement in their familiarity with clinical nephrology practice (median 2-point increase in familiarity score on a 7-point scale, P<0.001 by signed rank testing). Qualitative feedback included praise for the high-yield topics covered by the lectures and energizing teachers. In conclusion, we successfully implemented an ambulatory nephrology curriculum using a framework that integrated formal didactics, interactive online learning, and key clinical components of outpatient nephrology care. Future investigation will evaluate whether early implementation of this curriculum is associated with increased pursuit of nephrology as a career. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Prevalence of the prescription of potentially interacting drugs.

PubMed

Tragni, Elena; Casula, Manuela; Pieri, Vasco; Favato, Giampiero; Marcobelli, Alberico; Trotta, Maria Giovanna; Catapano, Alberico Luigi

2013-01-01

The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes "two prescriptions in the same day", and concomitant medication "the prescription of two drugs with overlapping coverage". A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.

Therapeutic Risk and Benefits of Concomitantly Using Herbal Medicines and Conventional Medicines: From the Perspectives of Evidence Based on Randomized Controlled Trials and Clinical Risk Management

PubMed Central

Zhang, Xiu-lai; Chen, Meng; Zhu, Ling-ling

2017-01-01

Despite increased awareness of the potential of herb-drug interactions (HDIs), the lack of rigorous clinical evidence regarding the significance provides a challenge for clinicians and consumers to make rational decisions about the safe combination of herbal and conventional medicines. This review addressed HDIs based on evidence from randomized controlled trials (RCTs). Literature was identified by performing a PubMed search till January 2017. Risk description and clinical risk management were described. Among 74 finally included RCTs, 17 RCTs (22.97%) simply addressed pharmacodynamic HDIs. Fifty-seven RCTs (77.03%) investigated pharmacokinetic HDIs and twenty-eight of them showed potential or actual clinical relevance. The extent of an HDI may be associated with the factors such as pharmacogenomics, dose of active ingredients in herbs, time course of interaction, characteristics of the object drugs (e.g., administration routes and pharmacokinetic profiles), modification of herbal prescription compositions, and coexistence of inducers and inhibitors. Clinical professionals should enhance risk management on HDIs such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant HDI by computerized reminder system, selecting the alternatives, adjusting dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation. PMID:28491115

Pathologic interactions in pulpal and periodontal tissues.

PubMed

Zehnder, M; Gold, S I; Hasselgren, G

2002-08-01

Both endodontic and periodontal disease are caused by a mixed anaerobic infection. The pathways for the spread of bacteria between pulpal and periodontal tissues have been discussed with controversy. This article is an attempt to provide a rational approach to the perio-endo/endo-perio question based on a review of the relevant literature. In the light of evidence, clinical concepts for the diagnosis and treatment of lesions involving both periodontal and pulpal tissues are discussed.

Routine drug and food interactions during antihelminthic treatment of neurocysticercosis: a reason for the variable efficacy of albendazole and praziquantel?

PubMed

Romo, Matthew L; Carpio, Arturo; Kelvin, Elizabeth A

2014-04-01

Neurocysticercosis (NC) or infection of the central nervous system with Taenia solium larvae is a leading cause of preventable seizures and epilepsy in endemic regions across the globe. Albendazole and praziquantel are commonly used antihelminthic agents to treat NC; however, viable cysts persist in the majority of patients, putting them at risk for future seizures and other neurological complications. Because of their pharmacokinetic profiles, albendazole and praziquantel have the potential to interact with many different drugs. During antihelminthic treatment, antiepileptic drugs and corticosteroids are commonly co-administered to manage seizures and cerebral edema; however, the most commonly used agents from these drug classes are known to significantly alter plasma concentrations of albendazole and praziquantel. The overarching issue with drug interactions during the treatment of NC is whether or not they have clinical relevance, as the plasma concentrations of albendazole and praziquantel have not been directly linked with eradication of viable cysts. Future studies should attempt to evaluate the validity of a causal relationship between antihelminthic plasma concentrations and outcomes so that drug interactions can be better understood and managed and so that treatment can be optimized. © 2014, The American College of Clinical Pharmacology.

Learning experience of Chinese nursing students in an online clinical English course: qualitative study.

PubMed

Tang, Anson C Y; Wong, Nick; Wong, Thomas K S

2015-02-01

The low English proficiency of Chinese nurse/nursing students affects their performance when they work in English-speaking countries. However, limited resources are available to help them improve their workplace English, i.e. English used in a clinical setting. To this end, it is essential to look for an appropriate and effective means to assist them in improving their clinical English. The objective of this study is to evaluate the learning experience of Chinese nursing students after they have completed an online clinical English course. Focus group interview was used to explore their learning experience. 100 students in nursing programs at Tung Wah College were recruited. The inclusion criteria were: (1) currently enrolled in a nursing program; and (2) having clinical experience. Eligible participants self-registered for the online English course, and were required to complete the course within 3 months. After that, semi-structured interviews were conducted on students whom completed the whole and less than half of the course. One of the researchers joined each of the interviews as a facilitator and an observer. Thematic analysis was used to analyze the data. Finally, 7 themes emerged from the interviews: technical issues, adequacy of support, time requirement, motivation, clarity of course instruction, course design, and relevancy of the course. Participants had varied opinions on the 2 themes: motivation and relevancy of the course. Overall, results of this study suggest that the online English course helped students improve their English. Factors which support their learning are interactive course design, no time constraint, and relevancy to their work/study. Factors which detracted from their learning are poor accessibility, poor technical and learning support and no peer support throughout the course. Copyright © 2014. Published by Elsevier Ltd.

An approach to evaluating drug-nutrient interactions.

PubMed

Santos, Cristina A; Boullata, Joseph I

2005-12-01

Although the significance of interactions between drugs is widely appreciated, little attention has been given to interactions between drugs and nutrients. Pharmacists are challenged to remember documented interactions involving available drugs, and they face the possibility that each newly approved therapeutic agent may be involved not only in unrecognized drug-drug interactions but in drug-nutrient interactions as well. A more consistent approach to evaluating drug-nutrient interactions is needed. The approach must be systematic in order to assess the influence of nutritional status, food, or specific nutrients on a drug's pharmacokinetics and pharmacodynamics, as well as the influence of a drug on overall nutritional status or on the status of a specific nutrient. We provide such a process, using several recently approved drugs as working examples. Risk factors and clinical relevance are described, with distinctions made between documented and potential interactions. Application of this process by the pharmacist to any drug will help increase their expertise. Furthermore, full consideration by pharmacists of all possible interactions of the drug regimens used in practice can allow for improved patient care.

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein-Protein Interaction Data.

PubMed

Pokharel, Yuba Raj; Saarela, Jani; Szwajda, Agnieszka; Rupp, Christian; Rokka, Anne; Lal Kumar Karna, Shibendra; Teittinen, Kaisa; Corthals, Garry; Kallioniemi, Olli; Wennerberg, Krister; Aittokallio, Tero; Westermarck, Jukka

2015-12-01

High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Publications in anesthesia journals: quality and clinical relevance.

PubMed

Lauritsen, Jakob; Moller, Ann M

2004-11-01

Clinicians performing evidence-based anesthesia rely on anesthesia journals for clinically relevant information. The objective of this study was to analyze the proportion of clinically relevant articles in five high impact anesthesia journals. We evaluated all articles published in Anesthesiology, Anesthesia & Analgesia, British Journal of Anesthesia, Anesthesia, and Acta Anaesthesiologica Scandinavica from January to June, 2000. Articles were assessed and classified according to type, outcome, and design; 1379 articles consisting of 5468 pages were evaluated and categorized. The most common types of article were animal and laboratory research (31.2%) and randomized clinical trial (20.4%). A clinically relevant article was defined as an article that used a statistically valid method and had a clinically relevant end-point. Altogether 18.6% of the pages had as their subject matter clinically relevant trials. We compared the Journal Impact Factor (a measure of the number of citations per article in a journal) and the proportion of clinically relevant pages and found that they were inversely proportional to each other.

Study of obligations defined in agreements between parties involved in clinical trials of medicinal products in Bulgaria.

PubMed

N Getov, Ilko; Gocheva-Hristova, Tanya; Lebanova, Hristina V; Grigorov, Evgeni E

2012-08-01

To analyse and assess the legislative and contractual obligations of the parties involved in the conduct of clinical trials, with identification of the needs for comprehensive contractual regulation of their rights and responsibilities. This survey has been carried out by means of review, analysis of comprehensiveness, comparative legislative analysis and assessment of compliance with the legislation of sample of investigator and site agreements governing the process of conducting clinical trials. The survey comprises analyses of contractual relations between the sponsor of the study and the investigator, and between the sponsor of the study and the trial site, respectively, relevant to clinical trials which are actually conducted in Bulgaria at the time of and following the survey. Comparative method based on pre-defined structured indices was employed to outline the major variances in the volume of responsibilities and obligations of the said parties to the clinical trial, as regulated by the investigator and site agreements. The analysis of comprehensiveness showed evident omissions in the regulation of relations and interactions between the parties to the agreements. The detailed contractual regulation providing for the statutory obligations and responsibilities of the parties involved in the conduct of clinical trials is a good guarantee for proper understanding of the obligations of each party and for compliance with their relevant responsibilities in view of protecting the rights of the participants in the clinical trials - patients or healthy volunteers.

The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017).

PubMed

Golan, Talia; Milella, Michele; Ackerstein, Aliza; Berger, Ranaan

2017-12-28

In the past decade, the oncology community has witnessed major advances in the understanding of cancer biology and major breakthroughs in several different therapeutic areas, from solid tumors to hematological malignancies; moreover, the advent of effective immunotherapy approaches, such as immune-checkpoint blockade, is revolutionizing treatment algorithms in almost all oncology disease areas. As knowledge evolves and new weapons emerge in the "war against cancer", clinical and translational research need to adapt to a rapidly changing environment to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients.With this in mind, translational cancer researchers, oncology professionals, treatment experts, CRO and industry leaders, as well as patient representatives gathered in London, 16-17 March 2017, for The International Congress on Clinical Trials in Oncology and Hemato-Oncology (ICTO2017), to discuss the changing face of oncology clinical trials in the new era of personalized medicine and immuno-oncology. A wide range of topics, including clinical trial design in immuno-oncology, biomarker-oriented drug development paths, statistical design and endpoint selection, challenges in the design and conduct of personalized medicine clinical trials, risk-based monitoring, financing and reimbursement, as well as best operational practices, were discussed in an open, highly interactive format, favoring networking among all relevant stakeholders. The most relevant data, approaches and issues emerged and discussed during the conference are summarized in this report.

Specifying the non-specific factors underlying opioid analgesia: Expectancy, attention, and affect

PubMed Central

Atlas, Lauren Y.; Wielgosz, Joseph; Whittington, Robert A.; Wager, Tor D.

2013-01-01

Rationale Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as “nonspecific” factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes. Objectives To determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect. Methods We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy, or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation, or stimulus expectancy. Results Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images. Conclusions The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments. PMID:24096537

Looking for the Perfect Mentor.

PubMed

Sá, Ana Pinheiro; Teixeira-Pinto, Cristina; Veríssimo, Rafaela; Vilas-Boas, Andreia; Firmino-Machado, João

2015-01-01

The authors established the profile of the Internal Medicine clinical teachers in Portugal aiming to define a future interventional strategy plan as adequate as possible to the target group and to the problems identified by the residents. Observational, transversal, analytic study. An online anonymous questionnaire was defined, evaluating the demographic characteristics of the clinical teachers, their path in Internal Medicine and their involvement in the residents learning process. We collected 213 valid questionnaires, making for an estimated response rate of 28.4%. Median global satisfaction with the clinical teacher was 4.52 (± 1.33 points) and the classification of the relationship between resident and clinical teacher was 4.86 ± 1.04 points. The perfect clinical teacher is defined by high standards of dedication and responsibility (4.9 ± 1.37 points), practical (4.8 ± 1.12 points) and theoretical skills (4.8 ± 1.07 points). The multiple linear regression model allowed to determine predictors of the residentâs satisfaction with their clinical teacher, justifying 82,5% of the variation of satisfaction with the clinical teacher (R2 = 0.83; R2 a = 0.82). Postgraduate medical education consists of an interaction between several areas of knowledge and intervening variables in the learning process having the clinical teacher in the central role. Overall, the pedagogical abilities were the most valued by the Internal Medicine residents regarding their clinical teacher, as determinants of a quality residentship. This study demonstrates the critical relevance of the clinical teacher in the satisfaction of residents with their residentship. The established multiple linear regression model highlights the impact of the clinical and pedagogical relantionship with the clinical teacher in a relevant increase in the satisfaction with the latter.

Hunter disease eClinic: interactive, computer-assisted, problem-based approach to independent learning about a rare genetic disease

PubMed Central

2010-01-01

Background Computer-based teaching (CBT) is a well-known educational device, but it has never been applied systematically to the teaching of a complex, rare, genetic disease, such as Hunter disease (MPS II). Aim To develop interactive teaching software functioning as a virtual clinic for the management of MPS II. Implementation and Results The Hunter disease eClinic, a self-training, user-friendly educational software program, available at the Lysosomal Storage Research Group (http://www.lysosomalstorageresearch.ca), was developed using the Adobe Flash multimedia platform. It was designed to function both to provide a realistic, interactive virtual clinic and instantaneous access to supporting literature on Hunter disease. The Hunter disease eClinic consists of an eBook and an eClinic. The eClinic is the interactive virtual clinic component of the software. Within an environment resembling a real clinic, the trainee is instructed to perform a medical history, to examine the patient, and to order appropriate investigation. The program provides clinical data derived from the management of actual patients with Hunter disease. The eBook provides instantaneous, electronic access to a vast collection of reference information to provide detailed background clinical and basic science, including relevant biochemistry, physiology, and genetics. In the eClinic, the trainee is presented with quizzes designed to provide immediate feedback on both trainee effectiveness and efficiency. User feedback on the merits of the program was collected at several seminars and formal clinical rounds at several medical centres, primarily in Canada. In addition, online usage statistics were documented for a 2-year period. Feedback was consistently positive and confirmed the practical benefit of the program. The online English-language version is accessed daily by users from all over the world; a Japanese translation of the program is also available. Conclusions The Hunter disease eClinic employs a CBT model providing the trainee with realistic clinical problems, coupled with comprehensive basic and clinical reference information by instantaneous access to an electronic textbook, the eBook. The program was rated highly by attendees at national and international presentations. It provides a potential model for use as an educational approach to other rare genetic diseases. PMID:20973983

Public-academic partnerships: research in community mental health settings: a practicum experience for researchers.

PubMed

Miller, Alexander L; Lopez, Linda; Gonzalez, Jodi M; Dassori, Albana; Bond, Gary; Velligan, Dawn

2008-11-01

Applying research findings to community mental health practices is slowed by provider concerns that research participants often differ from community populations in duration of illness, comorbid conditions, and illness severity. Selecting participants from community settings makes research results demonstrably relevant, but researchers and community providers can be mistrustful of one another, feeling that the other has little understanding of their needs and work. This mistrust impedes patient referrals for research. This column describes a program to increase researcher knowledge of community clinic procedures through structured interactions with clinic personnel. Follow-up interviews indicate improved attitudes and cooperation of researchers and community providers.

Patho-biotechnology; using bad bugs to make good bugs better.

PubMed

Sleator, Roy D; Hill, Colin

2007-01-01

Given the increasing commercial and clinical relevance of probiotic cultures, improving their stress tolerance profile and ability to overcome the physiochemical defences of the host is an important biological goal. Pathogenic bacteria have evolved sophisticated strategies to overcome host defences, interact with the immune system and interfere with essential host systems. We coin the term 'patho-biotechnology' to describe the exploitation of these valuable traits in biotechnology and biomedicine. This approach shows promise for the design of more technologically robust and effective probiotic cultures with improved biotechnological and clinical applications as well as the development of novel vaccine and drug delivery platforms.

The SADI Personal Health Lens: A Web Browser-Based System for Identifying Personally Relevant Drug Interactions.

PubMed

Vandervalk, Ben; McCarthy, E Luke; Cruz-Toledo, José; Klein, Artjom; Baker, Christopher J O; Dumontier, Michel; Wilkinson, Mark D

2013-04-05

The Web provides widespread access to vast quantities of health-related information that can improve quality-of-life through better understanding of personal symptoms, medical conditions, and available treatments. Unfortunately, identifying a credible and personally relevant subset of information can be a time-consuming and challenging task for users without a medical background. The objective of the Personal Health Lens system is to aid users when reading health-related webpages by providing warnings about personally relevant drug interactions. More broadly, we wish to present a prototype for a novel, generalizable approach to facilitating interactions between a patient, their practitioner(s), and the Web. We utilized a distributed, Semantic Web-based architecture for recognizing personally dangerous drugs consisting of: (1) a private, local triple store of personal health information, (2) Semantic Web services, following the Semantic Automated Discovery and Integration (SADI) design pattern, for text mining and identifying substance interactions, (3) a bookmarklet to trigger analysis of a webpage and annotate it with personalized warnings, and (4) a semantic query that acts as an abstract template of the analytical workflow to be enacted by the system. A prototype implementation of the system is provided in the form of a Java standalone executable JAR file. The JAR file bundles all components of the system: the personal health database, locally-running versions of the SADI services, and a javascript bookmarklet that triggers analysis of a webpage. In addition, the demonstration includes a hypothetical personal health profile, allowing the system to be used immediately without configuration. Usage instructions are provided. The main strength of the Personal Health Lens system is its ability to organize medical information and to present it to the user in a personalized and contextually relevant manner. While this prototype was limited to a single knowledge domain (drug/drug interactions), the proposed architecture is generalizable, and could act as the foundation for much richer personalized-health-Web clients, while importantly providing a novel and personalizable mechanism for clinical experts to inject their expertise into the browsing experience of their patients in the form of customized semantic queries and ontologies.

The SADI Personal Health Lens: A Web Browser-Based System for Identifying Personally Relevant Drug Interactions

PubMed Central

Vandervalk, Ben; McCarthy, E Luke; Cruz-Toledo, José; Klein, Artjom; Baker, Christopher J O; Dumontier, Michel

2013-01-01

Background The Web provides widespread access to vast quantities of health-related information that can improve quality-of-life through better understanding of personal symptoms, medical conditions, and available treatments. Unfortunately, identifying a credible and personally relevant subset of information can be a time-consuming and challenging task for users without a medical background. Objective The objective of the Personal Health Lens system is to aid users when reading health-related webpages by providing warnings about personally relevant drug interactions. More broadly, we wish to present a prototype for a novel, generalizable approach to facilitating interactions between a patient, their practitioner(s), and the Web. Methods We utilized a distributed, Semantic Web-based architecture for recognizing personally dangerous drugs consisting of: (1) a private, local triple store of personal health information, (2) Semantic Web services, following the Semantic Automated Discovery and Integration (SADI) design pattern, for text mining and identifying substance interactions, (3) a bookmarklet to trigger analysis of a webpage and annotate it with personalized warnings, and (4) a semantic query that acts as an abstract template of the analytical workflow to be enacted by the system. Results A prototype implementation of the system is provided in the form of a Java standalone executable JAR file. The JAR file bundles all components of the system: the personal health database, locally-running versions of the SADI services, and a javascript bookmarklet that triggers analysis of a webpage. In addition, the demonstration includes a hypothetical personal health profile, allowing the system to be used immediately without configuration. Usage instructions are provided. Conclusions The main strength of the Personal Health Lens system is its ability to organize medical information and to present it to the user in a personalized and contextually relevant manner. While this prototype was limited to a single knowledge domain (drug/drug interactions), the proposed architecture is generalizable, and could act as the foundation for much richer personalized-health-Web clients, while importantly providing a novel and personalizable mechanism for clinical experts to inject their expertise into the browsing experience of their patients in the form of customized semantic queries and ontologies. PMID:23612187

Cytochrome P450 enzyme mediated herbal drug interactions (Part 2)

PubMed Central

Wanwimolruk, Sompon; Phopin, Kamonrat; Prachayasittikul, Virapong

2014-01-01

To date, a number of significant herbal drug interactions have their origins in the alteration of cytochrome P450 (CYP) activity by various phytochemicals. Among the most noteworthy are those involving St. John's wort and drugs metabolized by human CYP3A4 enzyme. This review article is the continued work from our previous article (Part 1) published in this journal (Wanwimolruk and Prachayasittikul, 2014[ref:133]). This article extends the scope of the review to six more herbs and updates information on herbal drug interactions. These include black cohosh, ginseng, grape seed extract, green tea, kava, saw palmetto and some important Chinese medicines are also presented. Even though there have been many studies to determine the effects of herbs and herbal medicines on the activity of CYP, most of them were in vitro and in animal studies. Therefore, the studies are limited in predicting the clinical relevance of herbal drug interactions. It appeared that the majority of the herbal medicines have no clear effects on most of the CYPs examined. For example, the existing clinical trial data imply that black cohosh, ginseng and saw palmetto are unlikely to affect the pharmacokinetics of conventional drugs metabolized by human CYPs. For grape seed extract and green tea, adverse herbal drug interactions are unlikely when they are concomitantly taken with prescription drugs that are CYP substrates. Although there were few clinical studies on potential CYP-mediated interactions produced by kava, present data suggest that kava supplements have the ability to inhibit CYP1A2 and CYP2E1 significantly. Therefore, caution should be taken when patients take kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance their therapeutic and adverse effects. Despite the long use of traditional Chinese herbal medicines, little is known about the potential drug interactions with these herbs. Many popularly used Chinese medicines have been shown in vitro to significantly change the activity of human CYP. However, with little confirming evidence from clinical studies, precaution should be exercised when patients are taking Chinese herbal medicines concomitantly with drugs that are CYP substrates. Currently there is sufficient evidence to indicate that herbal drug interactions can occur and may lead to serious clinical consequence. Further clinical trial research should be conducted to verify these herbal drug interactions. Education on herbal drug interactions and communication with patients on their use of herbal products is also important. PMID:26417310

[From stone-craved genes to Michelangelo: significance and different aspects of gene-environment interaction].

PubMed

Lazary, Judit

2017-12-01

Although genetic studies have improved a lot in recent years, without clinical relevance sometimes their significance is devalued. Reviewing the major milestones of psychogenomics it can be seen that break-through success is just a question of time. Investigations of direct effect of genetic variants on phenotypes have not yielded positive findings. However, an important step was taken by adapting the gene-environment interaction model. In this model genetic vulnerability stepped into the place of "stone craved" pathology. Further progress happened when studies of environmental factors were combined with genetic function (epigenetics). This model provided the possibility for investigation of therapeutic interventions as environmental factors and it was proven that effective treatments exert a modifying effect on gene expression. Moreover, recent developments focus on therapeutic manipulation of gene function (e.g. chemogenetics). Instead of "stone craved" genes up-to-date dynamically interacting gene function became the basis of psychogenomics in which correction of the expression is a potential therapeutic tool. Keeping in mind these trends and developments, there is no doubt that genetics will be a fundamental part of daily clinical routine in the future.

Interactions between non-steroidal anti-inflammatory drugs and lipid membranes

NASA Astrophysics Data System (ADS)

Boggara, Mohan; Krishnamoorti, Ramanan

2008-03-01

Chronic usage of Non-steroidal anti-inflammatory drugs(NSAIDs) leads to gastrointestinal toxicity and clinical evidences point the cause to direct interactions between NSAIDs and phospholipid membranes. Also, NSAIDs pre-associated with phospholipid vesicles are shown to be safer and therapeutically more effective than unmodified ones. Our initial experiments and simulations on the partitioning of Aspirin and Ibuprofen clearly indicate role played by the drug structure in drug-membrane interactions. Those results motivated systematic molecular dynamics simulations of membranes with NSAIDs of different size, structure and pKa values. Our results suggest high partition coefficients for these NSAIDs in the membrane compared to water and thinning effect on the bilayer. Our small angle neutron scattering and reflectivity studies on DMPC-Ibuprofen systems indicate that the drug affects both ˜5 nm thick bilayer and overall ˜100 nm diameter vesicle, indicating that NSAIDs affect vesicles on various length scales. We will discuss the structural perturbations to membranes due to NSAIDs at clinically relevant molar ratios and their implications on the use of vesicles as delivery vehicles for NSAIDs.

Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1

PubMed Central

Cantor, Sharon B; Guillemette, Shawna

2011-01-01

It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1–FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression. PMID:21345144

Molecular interactions between general anesthetics and the 5HT2B receptor.

PubMed

Matsunaga, Felipe; Gao, Lu; Huang, Xi-Ping; Saven, Jeffery G; Roth, Bryan L; Liu, Renyu

2015-01-01

Serotonin modulates many processes through a family of seven serotonin receptors. However, no studies have screened for interactions between general anesthetics currently in clinical use and serotonergic G-protein-coupled receptors (GPCRs). Given that both intravenous and inhalational anesthetics have been shown to target other classes of GPCRs, we hypothesized that general anesthetics might interact directly with some serotonin receptors and thus modify their function. Radioligand binding assays were performed to screen serotonin receptors for interactions with propofol and isoflurane as well as for affinity determinations. Docking calculations using the crystal structure of 5-HT2B were performed to computationally confirm the binding assay results and locate anesthetic binding sites. The 5-HT2B class of receptors interacted significantly with both propofol and isoflurane in the primary screen. The affinities for isoflurane and propofol were determined to be 7.78 and .95 μM, respectively, which were at or below the clinical concentrations for both anesthetics. The estimated free energy derived from docking calculations for propofol (-6.70 kcal/mol) and isoflurane (-5.10 kcal/mol) correlated with affinities from the binding assay. The anesthetics were predicted to dock at a pharmacologically relevant binding site of 5HT2B. The molecular interactions between propofol and isoflurane with the 5-HT2B class of receptors were discovered and characterized. This finding implicates the serotonergic GPCRs as potential anesthetic targets.

Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer.

PubMed

van Leeuwen, Roelof W F; Peric, Robert; Hussaarts, Koen G A M; Kienhuis, Emma; IJzerman, Nikki S; de Bruijn, Peter; van der Leest, Cor; Codrington, Henk; Kloover, Jeroen S; van der Holt, Bronno; Aerts, Joachim G; van Gelder, Teun; Mathijssen, Ron H J

2016-04-20

Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib. © 2016 by American Society of Clinical Oncology.

Muscle-related side-effects of statins: from mechanisms to evidence-based solutions.

PubMed

Taylor, Beth A; Thompson, Paul D

2015-06-01

This article highlights the recent findings regarding statin-associated muscle side effects, including mechanisms and treatment as well as the need for more comprehensive clinical trials in statin myalgia. Statin myalgia is difficult to diagnose and treat, as major clinical trials have not routinely assessed muscle side-effects, there are few clinically relevant biomarkers and assessment tools for the symptoms, many apparent statin-related muscle symptoms may be nonspecific and related to other drugs or health conditions, and prevalence estimates vary widely. Data thus suggest that only 30-50% of patients with self-reported statin myalgia actually experience muscle pain on statins during blinded, placebo-controlled trials. In addition, evidence to date involving mechanisms underlying statin myalgia and its range of symptoms and presentations supports the hypothesis that there are multiple, interactive and potentially additive mechanisms underlying statin-associated muscle side-effects. There are likely multiple and interactive mechanisms underlying statin myalgia, and recent studies have produced equivocal data regarding prevalence of statin-associated muscle side-effects, contributing factors and effectiveness of common interventions. Therefore, more clinical trials on statin myalgia are critical to the field, as are systematic resources for quantifying, predicting and reporting statin-associated muscle side-effects.

Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration

PubMed Central

Trachtenberg, Jordan E.; Vo, Tiffany N.; Mikos, Antonios G.

2014-01-01

Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth. PMID:25319726

Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration.

PubMed

Trachtenberg, Jordan E; Vo, Tiffany N; Mikos, Antonios G

2015-03-01

Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth.

Biological nitric oxide signalling: chemistry and terminology

PubMed Central

Heinrich, Tassiele A; da Silva, Roberto S; Miranda, Katrina M; Switzer, Christopher H; Wink, David A; Fukuto, Jon M

2013-01-01

Biological nitrogen oxide signalling and stress is an area of extreme clinical, pharmacological, toxicological, biochemical and chemical research interest. The utility of nitric oxide and derived species as signalling agents is due to their novel and vast chemical interactions with a variety of biological targets. Herein, the chemistry associated with the interaction of the biologically relevant nitrogen oxide species with fundamental biochemical targets is discussed. Specifically, the chemical interactions of nitrogen oxides with nucleophiles (e.g. thiols), metals (e.g. hemeproteins) and paramagnetic species (e.g. dioxygen and superoxide) are addressed. Importantly, the terms associated with the mechanisms by which NO (and derived species) react with their respective biological targets have been defined by numerous past chemical studies. Thus, in order to assist researchers in referring to chemical processes associated with nitrogen oxide biology, the vernacular associated with these chemical interactions is addressed. PMID:23617570

Relevance of the nature vs nurture debate to clinical nursing.

PubMed

McVicar, A; Clancy, J

The philosophy of holistic care underpins nurse education, and the 'nature-nurture debate' is frequently used to facilitate discussion regarding the influence of interactions with the environment in 'shaping' the individual. A limitation to this approach is that much of the work cited in the literature relates primarily to psychosocial interactions. This conveys a narrow perspective on holism, and creates an impression that the debate cannot be applied to other aspects of health and wellbeing, yet models of nursing care emphasize the need for nurses to appreciate the interactional basis of health. This article uses examples from mental health, physical health and the influence of ageing, to argue that interactions must be viewed from a much wider perspective. Only in doing so can the principles and application of holistic care, and an understanding of the bases of health education practices, be appreciated.

To Compare PubMed Clinical Queries and UpToDate in Teaching Information Mastery to Clinical Residents: A Crossover Randomized Controlled Trial

PubMed Central

Sayyah Ensan, Ladan; Faghankhani, Masoomeh; Javanbakht, Anna; Ahmadi, Seyed-Foad; Baradaran, Hamid Reza

2011-01-01

Purpose To compare PubMed Clinical Queries and UpToDate regarding the amount and speed of information retrieval and users' satisfaction. Method A cross-over randomized trial was conducted in February 2009 in Tehran University of Medical Sciences that included 44 year-one or two residents who participated in an information mastery workshop. A one-hour lecture on the principles of information mastery was organized followed by self learning slide shows before using each database. Subsequently, participants were randomly assigned to answer 2 clinical scenarios using either UpToDate or PubMed Clinical Queries then crossed to use the other database to answer 2 different clinical scenarios. The proportion of relevantly answered clinical scenarios, time to answer retrieval, and users' satisfaction were measured in each database. Results Based on intention-to-treat analysis, participants retrieved the answer of 67 (76%) questions using UpToDate and 38 (43%) questions using PubMed Clinical Queries (P<0.001). The median time to answer retrieval was 17 min (95% CI: 16 to 18) using UpToDate compared to 29 min (95% CI: 26 to 32) using PubMed Clinical Queries (P<0.001). The satisfaction with the accuracy of retrieved answers, interaction with UpToDate and also overall satisfaction were higher among UpToDate users compared to PubMed Clinical Queries users (P<0.001). Conclusions For first time users, using UpToDate compared to Pubmed Clinical Querries can lead to not only a higher proportion of relevant answer retrieval within a shorter time, but also a higher users' satisfaction. So, addition of tutoring pre-appraised sources such as UpToDate to the information mastery curricula seems to be highly efficient. PMID:21858142

To compare PubMed Clinical Queries and UpToDate in teaching information mastery to clinical residents: a crossover randomized controlled trial.

PubMed

Sayyah Ensan, Ladan; Faghankhani, Masoomeh; Javanbakht, Anna; Ahmadi, Seyed-Foad; Baradaran, Hamid Reza

2011-01-01

To compare PubMed Clinical Queries and UpToDate regarding the amount and speed of information retrieval and users' satisfaction. A cross-over randomized trial was conducted in February 2009 in Tehran University of Medical Sciences that included 44 year-one or two residents who participated in an information mastery workshop. A one-hour lecture on the principles of information mastery was organized followed by self learning slide shows before using each database. Subsequently, participants were randomly assigned to answer 2 clinical scenarios using either UpToDate or PubMed Clinical Queries then crossed to use the other database to answer 2 different clinical scenarios. The proportion of relevantly answered clinical scenarios, time to answer retrieval, and users' satisfaction were measured in each database. Based on intention-to-treat analysis, participants retrieved the answer of 67 (76%) questions using UpToDate and 38 (43%) questions using PubMed Clinical Queries (P<0.001). The median time to answer retrieval was 17 min (95% CI: 16 to 18) using UpToDate compared to 29 min (95% CI: 26 to 32) using PubMed Clinical Queries (P<0.001). The satisfaction with the accuracy of retrieved answers, interaction with UpToDate and also overall satisfaction were higher among UpToDate users compared to PubMed Clinical Queries users (P<0.001). For first time users, using UpToDate compared to Pubmed Clinical Queries can lead to not only a higher proportion of relevant answer retrieval within a shorter time, but also a higher users' satisfaction. So, addition of tutoring pre-appraised sources such as UpToDate to the information mastery curricula seems to be highly efficient.

Better infrastructure for critical care trials: nomenclature, etymology, and informatics.

PubMed

Singh, Jeffrey M; Ferguson, Niall D

2009-01-01

The goals of this review article are to review the importance and value of standardized definitions in clinical research, as well as to propose the necessary tools and infrastructure needed to advance nosology and medial taxonomy to improve the quality of clinical trials in the field of critical care. We searched MEDLINE for relevant articles, reviewed those selected and their reference lists, and consulted personal files for relevant information. When the pathobiology of diseases is well understood, standard disease definitions can be extremely specific and precise; however, when the pathobiology of the disease is less well understood or more complex, biological markers may not be diagnostically useful or even available. In these cases, syndromic definitions effectively classify and group illnesses with similar symptoms and clinical signs. There is no clear gold standard for the diagnosis of many clinical entities in the intensive care unit, including notably both acute respiratory distress syndrome and sepsis. There are several types of consensus methods that can be used to explicate the judgmental approach that is often needed in these cases, including interactive or consensus groups, the nominal group technique, and the Delphi technique. Ideally, the definition development process will create clear and unambiguous language in which each definition accurately reflects the current understanding of the disease state. The development, implementation, evaluation, revision, and reevaluation of standardized definitions are keys for advancing the quality of clinical trials in the critical care arena.

Decision Support Tools for Clinical Diagnosis of Disease in Cows with Suspected Bovine Spongiform Encephalopathy

PubMed Central

Saegerman, C.; Speybroeck, N.; Roels, S.; Vanopdenbosch, E.; Thiry, E.; Berkvens, D.

2004-01-01

Reporting of clinically suspected cattle is currently the most common method for detecting cases of bovine spongiform encephalopathy (BSE). Improvement of clinical diagnosis and decision-making remains crucial. A comparison of clinical patterns, consisting of 25 signs, was made between all 30 BSE cases, confirmed in Belgium before October 2002, and 272 suspected cases that were subsequently determined to be histologically, immunohistochemically, and scrapie-associated-fiber negative. Seasonality in reporting suspected cases was observed, with more cases being reported during wintertime when animals were kept indoors. The median duration of illness was 30 days. The 10 most relevant signs of BSE were kicking in the milking parlor, hypersensitivity to touch and/or sound, head shyness, panic-stricken response, reluctance to enter in the milking parlor, abnormal ear movement or carriage, increased alertness behavior, reduced milk yield, teeth grinding, and temperament change. Ataxia did not appear to be a specific sign of BSE. A classification and regression tree was constructed by using the following four features: age of the animal, year of birth, number of relevant BSE signs noted, and number of clinical signs, typical for listeriosis, noted. The model had a sensitivity of 100% and a specificity of 85%. This approach allows the use of an interactive decision-support tool, based entirely on odds ratios, a statistic independent of disease prevalence. PMID:14715749

A partial hearing animal model for chronic electro-acoustic stimulation

NASA Astrophysics Data System (ADS)

Irving, S.; Wise, A. K.; Millard, R. E.; Shepherd, R. K.; Fallon, J. B.

2014-08-01

Objective. Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. Approach. This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. Main results. Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. Significance. This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual hearing following cochlear implantation. The ability to record CAPs via the CI has clinical direct relevance for obtaining objective measures of residual hearing.

Nurses' decision-making in ethically relevant clinical situations using the example of breathlessness: study protocol of a reflexive grounded theory integrating Goffman's framework analysis.

PubMed

Dunger, Christine; Schnell, Martin W; Bausewein, Claudia

2017-02-22

Decision-making (DM) in healthcare can be understood as an interactive process addressing decision makers' reasoning as well as their visible behaviour after the decision is made. Other key elements of DM are ethical aspects and the role as well as the treatment options of the examined professions. Nurses' DM to choose interventions in situations of severe breathlessness is such interactions. They are also ethically relevant regarding the vulnerability of affected patients and possible restrictions or treatment options. The study aims to explore which factors influence nurses' DM to use nursing interventions in situations where patients suffer from severe breathlessness. Qualitative study including nurses in German hospital wards and hospices. A triangulation of different methods of data collection-participant observation and qualitative expert interviews-and analysis merge in a reflexive grounded theory approach which integrates Goffman's framework analysis. It allows an analysis of nurses' self-statements about DM, their behaviour in relevant clinical situations and its influences. Data collection and analysis will be examined simultaneously. Informed consent will be gained from all participants and the institutional stakeholders. Ongoing consent has to be ensured since observations will take place in healthcare institutions and many patients will be highly vulnerable. The study has been evaluated and approved by the Witten/Herdecke University Ethics Committee, Witten, Germany. Results of the study will be published at congresses and in journal papers. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Cross Talk: The Microbiota and Neurodevelopmental Disorders

PubMed Central

Kelly, John R.; Minuto, Chiara; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.

2017-01-01

Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance. PMID:28966571

Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons.

PubMed

Jayaraman, Anusha; Pike, Christian J

2014-03-25

Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Measuring treatment effects on dual-task performance: a framework for research and clinical practice

PubMed Central

Plummer, Prudence; Eskes, Gail

2015-01-01

The relevance of dual-task walking to everyday ambulation is widely acknowledged, and numerous studies have demonstrated that dual-task interference can significantly impact recovery of functional walking in people with neurological disorders. The magnitude and direction of dual-task interference is influenced by the interaction between the two tasks, including how individuals spontaneously prioritize their attention. Therefore, to accurately interpret and characterize dual-task interference and identify changes over time, it is imperative to evaluate single and dual-task performance in both tasks, as well as the tasks relative to each other. Yet, reciprocal dual-task effects (DTE) are frequently ignored. The purpose of this perspective paper is to present a framework for measuring treatment effects on dual-task interference, specifically taking into account the interactions between the two tasks and how this can provide information on whether overall dual-task capacity has improved or a different attentional strategy has been adopted. In discussing the clinical implications of using this framework, we provide specific examples of using this method and provide some explicit recommendations for research and clinical practice. PMID:25972801

Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine – searching for the connections

PubMed Central

Danysz, Wojciech; Parsons, Chris G

2012-01-01

β-amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Aβ has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release. As NMDA receptors are critically involved in neuronal plasticity including learning and memory, we felt that it would be valuable to provide an up to date review of the evidence connecting Aβ to these receptors and related neuronal plasticity. Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine. This substance is the only NMDA receptor antagonist used clinically in the treatment of AD and therefore offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility. PMID:22646481

The analysis of verbal interaction sequences in dyadic clinical communication: a review of methods.

PubMed

Connor, Martin; Fletcher, Ian; Salmon, Peter

2009-05-01

To identify methods available for sequential analysis of dyadic verbal clinical communication and to review their methodological and conceptual differences. Critical review, based on literature describing sequential analyses of clinical and other relevant social interaction. Dominant approaches are based on analysis of communication according to its precise position in the series of utterances that constitute event-coded dialogue. For practical reasons, methods focus on very short-term processes, typically the influence of one party's speech on what the other says next. Studies of longer-term influences are rare. Some analyses have statistical limitations, particularly in disregarding heterogeneity between consultations, patients or practitioners. Additional techniques, including ones that can use information about timing and duration of speech from interval-coding are becoming available. There is a danger that constraints of commonly used methods shape research questions and divert researchers from potentially important communication processes including ones that operate over a longer-term than one or two speech turns. Given that no one method can model the complexity of clinical communication, multiple methods, both quantitative and qualitative, are necessary. Broadening the range of methods will allow the current emphasis on exploratory studies to be balanced by tests of hypotheses about clinically important communication processes.

Healthcare professionals' agreement on clinical relevance of drug-related problems among elderly patients.

PubMed

Bech, Christine Flagstad; Frederiksen, Tine; Villesen, Christine Tilsted; Højsted, Jette; Nielsen, Per Rotbøll; Kjeldsen, Lene Juel; Nørgaard, Lotte Stig; Christrup, Lona Louring

2018-02-01

Background Disagreement among healthcare professionals on the clinical relevance of drug-related problems can lead to suboptimal treatment and increased healthcare costs. Elderly patients with chronic non-cancer pain and comorbidity are at increased risk of drug related problems compared to other patient groups due to complex medication regimes and transition of care. Objective To investigate the agreement among healthcare professionals on their classification of clinical relevance of drug-related problems in elderly patients with chronic non-cancer pain and comorbidity. Setting Multidisciplinary Pain Centre, Rigshospitalet, Copenhagen, Denmark. Method A pharmacist performed medication review on elderly patients with chronic non-cancer pain and comorbidity, identified their drug-related problems and classified these problems in accordance with an existing categorization system. A five-member clinical panel rated the drug-related problems' clinical relevance in accordance with a five-level rating scale, and their agreement was compared using Fleiss' κ. Main outcome measure Healthcare professionals' agreement on clinical relevance of drug related problems, using Fleiss' κ. Results Thirty patients were included in the study. A total of 162 drug related problems were identified, out of which 54% were of lower clinical relevance (level 0-2) and 46% of higher clinical relevance (level 3-4). Only slight agreement (κ = 0.12) was found between the panellists' classifications of clinical relevance using a five-level rating scale. Conclusion The clinical pharmacist identified drug related problems of lower and higher clinical relevance. Poor overall agreement on the severity of the drug related problems was found among the panelists.

The effect of propofol on plasma membrane ultrastructure in the intact cells

NASA Astrophysics Data System (ADS)

Jin, Weixiang; Pralle, Arnd

The mechanism of general anesthesia is still unknown. One drug used for human anesthesia, propofol, has been shown to interact with some ligand gated ion-channels, but also easily dissolves in the lipid bilayer and alters fluidity. Which mechanism dominates or even how anesthesia arises are unclear. We study the influence of propofol on plasma membrane (PM) ultrastructure in intact cells. In the PM, transient submicroscopic nanodomains form by interactions between lipid-acyl-chains or lipid head groups, stabilized by cholesterol. In addition, membrane cytoskeleton further regulates the nanodomains, which then regulate signaling. We study transient propofol effects on these domains from low to clinically relevant propofol concentrations by analyzing diffusion of GFP-tagged outer leaflet/inner leaflet membrane proteins. Using bimFCS we measure diffusion on multiple length scales simultaneously. We observe that at low propofol concentrations, the nanodomains trap GPI-mGFP less, consistent with studies showing that propofol decreases the phase transition temperature of membrane derived vesicles. Interestingly, at clinical relevant concentrations of propofol, the nanodomains trap GPI-mGFP more strongly. This is only observed at 37C. By inhibiting myosin activity or actin filaments (de-)polymerization, we find that the activity of actin filaments further alters the behavior of cholesterol nanodomains due to propofol. We compare the effect of propofol and its analog confirming specificity.

Human Adipose Mesenchymal Cells Inhibit Melanocyte Differentiation and the Pigmentation of Human Skin via Increased Expression of TGF-β1.

PubMed

Klar, Agnes S; Biedermann, Thomas; Michalak, Katarzyna; Michalczyk, Teresa; Meuli-Simmen, Claudia; Scherberich, Arnaud; Meuli, Martin; Reichmann, Ernst

2017-12-01

There is accumulating evidence that interactions between epidermal melanocytes and stromal cells play an important role in the regulation of skin pigmentation. In this study we established a pigmented dermo-epidermal skin model, melDESS, of human origin to investigate the effects of distinct stromal cells on melanogenesis. melDESS is a complex, clinically relevant skin equivalent composed of an epidermis containing both melanocytes and keratinocytes. Its dermal compartment consists either of adipose tissue-derived stromal cells, dermal fibroblasts (Fbs), or a mixture of both cell types. These skin substitutes were transplanted for 5 weeks on the backs of immuno-incompetent rats and analyzed. Gene expression and Western blot analyses showed a significantly higher expression of transforming growth factor-β1 by adipose tissue-derived stromal cells compared with dermal Fbs. In addition, we showed that melanocytes responded to the increased levels of transforming growth factor-β1 by down-regulating the expression of key melanogenic enzymes such as tyrosinase. This caused decreased melanin synthesis and, consequently, greatly reduced pigmentation of melDESS. The conclusions are of utmost clinical relevance, namely that adipose tissue-derived stromal cells derived from the hypodermis fail to appropriately interact with epidermal melanocytes, thus preventing the sustainable restoration of the patient's native skin color in bioengineered skin grafts. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Interactive decision support in hepatic surgery

PubMed Central

Dugas, Martin; Schauer, Rolf; Volk, Andreas; Rau, Horst

2002-01-01

Background Hepatic surgery is characterized by complicated operations with a significant peri- and postoperative risk for the patient. We developed a web-based, high-granular research database for comprehensive documentation of all relevant variables to evaluate new surgical techniques. Methods To integrate this research system into the clinical setting, we designed an interactive decision support component. The objective is to provide relevant information for the surgeon and the patient to assess preoperatively the risk of a specific surgical procedure. Based on five established predictors of patient outcomes, the risk assessment tool searches for similar cases in the database and aggregates the information to estimate the risk for an individual patient. Results The physician can verify the analysis and exclude manually non-matching cases according to his expertise. The analysis is visualized by means of a Kaplan-Meier plot. To evaluate the decision support component we analyzed data on 165 patients diagnosed with hepatocellular carcinoma (period 1996–2000). The similarity search provides a two-peak distribution indicating there are groups of similar patients and singular cases which are quite different to the average. The results of the risk estimation are consistent with the observed survival data, but must be interpreted with caution because of the limited number of matching reference cases. Conclusion Critical issues for the decision support system are clinical integration, a transparent and reliable knowledge base and user feedback. PMID:12003639

Seven basic dimensions of personality pathology and their clinical consequences: Are all personalities equally harmful?

PubMed

Vall, Gemma; Gutiérrez, Fernando; Peri, Josep M; Gárriz, Miguel; Ferraz, Liliana; Baillés, Eva; Obiols, Jordi E

2015-11-01

Dimensional pathology models are increasingly being accepted for the assessment of disordered personalities, but their ability to predict negative outcomes is yet to be studied. We examine the relative clinical impact of seven basic dimensions of personality pathology through their associations with a wide range of clinical outcomes. A sample of 960 outpatients was assessed through a 7-factor model integrating the Cloninger, the Livesley, and the DSM taxonomies. Thirty-six indicators of clinical outcome covering three areas - dissatisfaction, functional difficulties, and clinical severity - were also assessed. The unique contribution of each personality dimension to clinical outcome was estimated through multiple regressions. Overall, personality dimensions explained 17.6% of the variance of clinical outcome, but varied substantially in terms of their unique contributions. Negative Emotionality had the greatest impact in all areas, contributing 43.9% of the explained variance. The remaining dimensions led to idiosyncratic patterns of clinical outcomes but had a comparatively minor clinical impact. A certain effect was also found for combinations of dimensions such as Negative Emotionality × Impulsive Sensation Seeking, but most interactions were clinically irrelevant. Our findings suggest that the most relevant dimensions of personality pathology are associated with very different clinical consequences and levels of harmfulness. The relative clinical impact of seven basic dimensions of personality pathology is examined. Negative Emotionality (Neuroticism) is 6-14 times as harmful as other pathological dimensions. The remaining dimensions and their interactions have very specific and comparatively minor clinical consequences. We examine only a handful of clinical outcomes. Our results may not be generalizable to other clinical or life outcomes. Our variables are self-reported and hence susceptible to bias. Our design does not allow us to establish causal relationships between personality and clinical outcomes. © 2015 The British Psychological Society.

A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

PubMed

Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

2015-04-01

Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

What counts as effective communication in nursing? Evidence from nurse educators' and clinicians' feedback on nurse interactions with simulated patients.

PubMed

O'Hagan, Sally; Manias, Elizabeth; Elder, Catherine; Pill, John; Woodward-Kron, Robyn; McNamara, Tim; Webb, Gillian; McColl, Geoff

2014-06-01

To examine the feedback given by nurse educators and clinicians on the quality of communication skills of nurses in interactions with simulated patients. The quality of communication in interactions between nurses and patients has a major influence on patient outcomes. To support the development of effective nursing communication in clinical practice, a good understanding of what constitutes effective communication is helpful. An exploratory design was used involving individual interviews, focus groups and written notes from participants and field notes from researchers to investigate perspectives on nurse-patient communication. Focus groups and individual interviews were held between August 2010-September 2011 with a purposive sample of 15 nurse educators and clinicians who observed videos of interactions between nurses and simulated patients. These participants were asked to give oral feedback on the quality and content of these interactions. Verbatim transcriptions were undertaken of all data collected. All written notes and field notes were also transcribed. Thematic analysis of the data was undertaken. Four major themes related to nurse-patient communication were derived from the educators' and clinicians' feedback: approach to patients and patient care, manner towards patients, techniques used for interacting with patients and generic aspects of communication. This study has added to previous research by contributing grounded evidence from a group of nurse educators and clinicians on the aspects of communication that are relevant for effective nurse-patient interactions in clinical practice. © 2013 John Wiley & Sons Ltd.

Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis.

PubMed

Kim, Soo-Hyun; Redvers, Richard P; Chi, Lap Hing; Ling, Xiawei; Lucke, Andrew J; Reid, Robert C; Fairlie, David P; Baptista Moreno Martin, Ana Carolina; Anderson, Robin L; Denoyer, Delphine; Pouliot, Normand

2018-05-21

Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. © 2018. Published by The Company of Biologists Ltd.

Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms.

PubMed

Manzardo, Ann M; McGuire, Austen; Butler, Merlin G

2015-04-15

Alcoholism arises from combined effects of multiple biological factors including genetic and non-genetic causes with gene/environmental interaction. Intensive research and advanced genetic technology has generated a long list of genes and biomarkers involved in alcoholism neuropathology. These markers reflect complex overlapping and competing effects of possibly hundreds of genes which impact brain structure, function, biochemical alcohol processing, sensitivity and risk for dependence. We compiled a tabular list of clinically relevant genetic biomarkers for alcoholism targeting expression disturbances in the human brain through an extensive search of keywords related to alcoholism, alcohol abuse, and genetics from peer reviewed medical research articles and related nationally sponsored websites. Gene symbols were then placed on high resolution human chromosome ideograms with gene descriptions in tabular form. We identified 337 clinically relevant genetic biomarkers and candidate genes for alcoholism and alcohol-responsiveness from human brain research. Genetic biomarkers included neurotransmitter pathways associated with brain reward processes for dopaminergic (e.g., DRD2, MAOA, and COMT), serotoninergic (e.g., HTR3A, HTR1B, HTR3B, and SLC6A4), GABAergic (e.g., GABRA1, GABRA2, and GABRG1), glutaminergic (GAD1, GRIK3, and GRIN2C) and opioid (e.g., OPRM1, OPRD1, and OPRK1) pathways which presumably impact reinforcing properties of alcohol. Gene level disturbances in cellular and molecular networks impacted by alcohol and alcoholism pathology include transketolase (TKT), transferrin (TF), and myelin (e.g., MBP, MOBP, and MOG). High resolution chromosome ideograms provide investigators, physicians, geneticists and counselors a convenient visual image of the distribution of alcoholism genetic biomarkers from brain research with alphabetical listing of genes in tabular form allowing comparison between alcoholism-related phenotypes, and clinically-relevant alcoholism gene(s) at the chromosome band level to guide research, diagnosis, and treatment. Chromosome ideograms may facilitate gene-based personalized counseling of alcohol dependent individuals and their families. Copyright © 2015 Elsevier B.V. All rights reserved.

Simple and efficient machine learning frameworks for identifying protein-protein interaction relevant articles and experimental methods used to study the interactions.

PubMed

Agarwal, Shashank; Liu, Feifan; Yu, Hong

2011-10-03

Protein-protein interaction (PPI) is an important biomedical phenomenon. Automatically detecting PPI-relevant articles and identifying methods that are used to study PPI are important text mining tasks. In this study, we have explored domain independent features to develop two open source machine learning frameworks. One performs binary classification to determine whether the given article is PPI relevant or not, named "Simple Classifier", and the other one maps the PPI relevant articles with corresponding interaction method nodes in a standardized PSI-MI (Proteomics Standards Initiative-Molecular Interactions) ontology, named "OntoNorm". We evaluated our system in the context of BioCreative challenge competition using the standardized data set. Our systems are amongst the top systems reported by the organizers, attaining 60.8% F1-score for identifying relevant documents, and 52.3% F1-score for mapping articles to interaction method ontology. Our results show that domain-independent machine learning frameworks can perform competitively well at the tasks of detecting PPI relevant articles and identifying the methods that were used to study the interaction in such articles. Simple Classifier is available at http://sourceforge.net/p/simpleclassify/home/ and OntoNorm at http://sourceforge.net/p/ontonorm/home/.

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency, clinical relevance and outcome.

PubMed

Trenkwalder, Teresa; Lahmann, Anna Lena; Nowicka, Magdalena; Pellegrini, Costanza; Rheude, Tobias; Mayr, N Patrick; Voss, Stephanie; Bleiziffer, Sabine; Lange, Rüdiger; Joner, Michael; Kasel, Albert M; Kastrati, Adnan; Schunkert, Heribert; Husser, Oliver; Hadamitzky, Martin; Hengstenberg, Christian

2018-02-21

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients' outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80 ± 7 vs. 80 ± 7 years; p = 0.198) and EuroSCORE II (3.6% [2.1-5.7] vs. 3.6% [2.1-5.9]; p = 0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p < 0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p = 0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n = 48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p = 0.339, 1-year: 11% vs. 14%; p = 0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.

Cytochrome P450 enzyme mediated herbal drug interactions (Part 1)

PubMed Central

Wanwimolruk, Sompon; Prachayasittikul, Virapong

2014-01-01

It is well recognized that herbal supplements or herbal medicines are now commonly used. As many patients taking prescription medications are concomitantly using herbal supplements, there is considerable risk for adverse herbal drug interactions. Such interactions can enhance the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index such as warfarin, cyclosporine A and digoxin. Herbal drug interactions can alter pharmacokinetic or/and pharmacodynamic properties of administered drugs. The most common pharmacokinetic interactions usually involve either the inhibition or induction of the metabolism of drugs catalyzed by the important enzymes, cytochrome P450 (CYP). The aim of the present article is to provide an updated review of clinically relevant metabolic CYP-mediated drug interactions between selected herbal supplements and prescription drugs. The commonly used herbal supplements selected include Echinacea, Ginkgo biloba, garlic, St. John's wort, goldenseal, and milk thistle. To date, several significant herbal drug interactions have their origins in the alteration of CYP enzyme activity by various phytochemicals. Numerous herbal drug interactions have been reported. Although the significance of many interactions is uncertain but several interactions, especially those with St. John’s wort, may have critical clinical consequences. St. John’s wort is a source of hyperforin, an active ingredient that has a strong affinity for the pregnane xenobiotic receptor (PXR). As a PXR ligand, hyperforin promotes expression of CYP3A4 enzymes in the small intestine and liver. This in turn causes induction of CYP3A4 and can reduce the oral bioavailability of many drugs making them less effective. The available evidence indicates that, at commonly recommended doses, other selected herbs including Echinacea, Ginkgo biloba, garlic, goldenseal and milk thistle do not act as potent or moderate inhibitors or inducers of CYP enzymes. A good knowledge of the mechanisms of herbal drug interactions is necessary for assessing and minimizing clinical risks. These processes help prediction of interactions between herbal supplements and prescription drugs. Healthcare professionals should remain vigilant for potential interactions between herbal supplements/medicines and prescription drugs, especially for drugs with a narrow therapeutic index are used. PMID:26417265

Reference intervals and allometric scaling of two-dimensional echocardiographic measurements in 150 healthy cats.

PubMed

Karsten, Schober; Stephanie, Savino; Vedat, Yildiz

2017-11-10

The objective of the study was to evaluate the effects of body weight (BW), breed, and sex on two-dimensional (2D) echocardiographic measures, reference ranges, and prediction intervals using allometrically-scaled data of left atrial (LA) and left ventricular (LV) size and LV wall thickness in healthy cats. Study type was retrospective, observational, and clinical cohort. 150 healthy cats were enrolled and 2D echocardiograms analyzed. LA diameter, LV wall thickness, and LV dimension were quantified using three different imaging views. The effect of BW, breed, sex, age, and interaction (BW*sex) on echocardiographic variables was assessed using univariate and multivariate regression and linear mixed model analysis. Standard (using raw data) and allometrically scaled (Y=a × M b ) reference intervals and prediction intervals were determined. BW had a significant (P<0.05) independent effect on 2D variables whereas breed, sex, and age did not. There were clinically relevant differences between reference intervals using mean ± 2SD of raw data and mean and 95% prediction interval of allometrically-scaled variables, most prominent in larger (>6 kg) and smaller (<3 kg) cats. A clinically relevant difference between thickness of the interventricular septum (IVS) and dimension of the LV posterior wall (LVPW) was identified. In conclusion, allometric scaling and BW-based 95% prediction intervals should be preferred over conventional 2D echocardiographic reference intervals in cats, in particular in small and large cats. These results are particularly relevant to screening examinations for feline hypertrophic cardiomyopathy.

Ahead of the game: the use of gaming to enhance knowledge of psychopharmacology.

PubMed

Beek, Terra S; Boone, Cheryl; Hubbard, Grace

2014-12-01

Experiential teaching strategies have the potential to more effectively help students with critical thinking than traditional lecture formats. Gaming is an experiential teaching-learning strategy that reinforces teamwork, interaction, and enjoyment and introduces the element of play. Two Bachelor of Science in Nursing students and a clinical instructor created a Jeopardy!(®)-style game to enhance understanding of psychopharmacology, foster student engagement in the learning process, and promote student enjoyment during clinical postconference. The current article evaluates the utility, relevance, and effectiveness of gaming using a Jeopardy!(®)-style format for the psychiatric clinical setting. Students identified the strengths of this learning activity as increased awareness of knowledge deficits, as well as the reinforcement of existing knowledge and the value of teamwork. Copyright 2014, SLACK Incorporated.

Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.

PubMed

Rietjens, Saskia J; Hondebrink, Laura; Westerink, Remco H S; Meulenbelt, Jan

2012-11-01

Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.

Non-obvious correlations to disease management unraveled by Bayesian artificial intelligence analyses of CMS data.

PubMed

Vemulapalli, Vijetha; Qu, Jiaqi; Garren, Jeonifer M; Rodrigues, Leonardo O; Kiebish, Michael A; Sarangarajan, Rangaprasad; Narain, Niven R; Akmaev, Viatcheslav R

2016-11-01

Given the availability of extensive digitized healthcare data from medical records, claims and prescription information, it is now possible to use hypothesis-free, data-driven approaches to mine medical databases for novel insight. The goal of this analysis was to demonstrate the use of artificial intelligence based methods such as Bayesian networks to open up opportunities for creation of new knowledge in management of chronic conditions. Hospital level Medicare claims data containing discharge numbers for most common diagnoses were analyzed in a hypothesis-free manner using Bayesian networks learning methodology. While many interactions identified between discharge rates of diagnoses using this data set are supported by current medical knowledge, a novel interaction linking asthma and renal failure was discovered. This interaction is non-obvious and had not been looked at by the research and clinical communities in epidemiological or clinical data. A plausible pharmacological explanation of this link is proposed together with a verification of the risk significance by conventional statistical analysis. Potential clinical and molecular pathways defining the relationship between commonly used asthma medications and renal disease are discussed. The study underscores the need for further epidemiological research to validate this novel hypothesis. Validation will lead to advancement in clinical treatment of asthma & bronchitis, thereby, improving patient outcomes and leading to long term cost savings. In summary, this study demonstrates that application of advanced artificial intelligence methods in healthcare has the potential to enhance the quality of care by discovering non-obvious, clinically relevant relationships and enabling timely care intervention. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Interpersonal Engagement Mediates the Relation between Maternal Affect and Externalising Behaviour in Young Children with Type 1 Diabetes

PubMed Central

Chisholm, Vivienne; Gonzalez, Andrea; Atkinson, Leslie

2014-01-01

Mother-child interactions around a shared activity have been shown to play a key role in the development of young children’s capacity to interact cooperatively with others. This evidence is particularly germane to type 1 diabetes (T1D) management in younger children where cooperation with parental treatment efforts is crucial for treatment success and where maternal distress and child behavioural problems are risk factors for treatment management, biomedical and psychological outcomes. In 49 4-to-8 year old children with T1D, we investigated whether the association between maternal affect and child problematic behaviour is mediated by mother-child interactions in the context of a T1D-relevant collaborative problem-solving activity. Mothers completed standardised measures of maternal and child psychological adjustment and interacted with their children in the problem-solving activity, analysed for quality of interpersonal engagement based on evaluations of maternal (sensitivity and cognitive stimulation) and dyadic (joint attention and warmth) behaviours. Mediation analyses confirmed the hypothesis that interpersonal engagement mediates the relation between maternal affective state and child behavioural problems. Specifically, more negative maternal affect is associated with lower levels of interpersonal engagement; these less engaged interactions in turn are associated with more behavioural problems in children. These findings are consistent with research involving typically developing children. The implications of our findings are twofold. First, in the context of psychological adjustment to T1D, maternal affect and mother-child interactions are 2 potential targets for interventions which promote cooperative interactions. Second, understanding and caring for children at biological risk requires attention to developmental psychology theory and method; in particular, research addressing parent-child cooperation carries both conceptual and clinical relevance. PMID:24905358

[Changes and differences of heart rate variability of patients in a psychiatric rehabilitation clinic].

PubMed

Riffer, Friedrich; Streibl, Lore; Sprung, Manuel; Kaiser, Elmar; Riffer, Lena

2016-12-01

A reduced heart rate variability (HRV) has been associated with various different pathological physical and psychological conditions and illnesses. The present study is focused on investigating HRV in respect to psychological disorders (depressive disorders anxiety disorders, Burn-out-Syndrome). The results from an investigation with patients from a psychiatric Rehabilitation clinic following a six week in-patient treatment are presented. The results show relevant changes in HRV in the course of the rehabilitative treatment for patients with depressive disorders, anxiety disorders or Burn-out-Syndrome. Simultaneously changes in HRV were linked with improvements in patient's psychological symptoms. Changes in HRV (i. e. an increase of relevant HRV-parameters) were accompanied by a reduction of psychological strain as well as psychological and physical health problems, which typically occur in Burnout-Syndrome. Furthermore, changes in relevant HRV-parameters were predictive of changes in psychological symptoms (depression, anxiety, phobia, Burnout symptoms). The present study did show, that in respect to the investigation of the relationship between HRV and subjective data, primarily those HRV-parameters are important (in terms of significant results) which are based on parasympathetic activity. These results are interesting in the context of theories, which view vagal mediated HRV as positively connected with self-regulation, adaptability and positive interpersonal interaction of individuals.

Social and emotional relevance in face processing: happy faces of future interaction partners enhance the late positive potential

PubMed Central

Bublatzky, Florian; Gerdes, Antje B. M.; White, Andrew J.; Riemer, Martin; Alpers, Georg W.

2014-01-01

Human face perception is modulated by both emotional valence and social relevance, but their interaction has rarely been examined. Event-related brain potentials (ERP) to happy, neutral, and angry facial expressions with different degrees of social relevance were recorded. To implement a social anticipation task, relevance was manipulated by presenting faces of two specific actors as future interaction partners (socially relevant), whereas two other face actors remained non-relevant. In a further control task all stimuli were presented without specific relevance instructions (passive viewing). Face stimuli of four actors (2 women, from the KDEF) were randomly presented for 1s to 26 participants (16 female). Results showed an augmented N170, early posterior negativity (EPN), and late positive potential (LPP) for emotional in contrast to neutral facial expressions. Of particular interest, face processing varied as a function of experimental tasks. Whereas task effects were observed for P1 and EPN regardless of instructed relevance, LPP amplitudes were modulated by emotional facial expression and relevance manipulation. The LPP was specifically enhanced for happy facial expressions of the anticipated future interaction partners. This underscores that social relevance can impact face processing already at an early stage of visual processing. These findings are discussed within the framework of motivated attention and face processing theories. PMID:25076881

Review of nanomaterials in dentistry: interactions with the oral microenvironment, clinical applications, hazards, and benefits.

PubMed

Besinis, Alexandros; De Peralta, Tracy; Tredwin, Christopher J; Handy, Richard D

2015-03-24

Interest in the use of engineered nanomaterials (ENMs) as either nanomedicines or dental materials/devices in clinical dentistry is growing. This review aims to detail the ultrafine structure, chemical composition, and reactivity of dental tissues in the context of interactions with ENMs, including the saliva, pellicle layer, and oral biofilm; then describes the applications of ENMs in dentistry in context with beneficial clinical outcomes versus potential risks. The flow rate and quality of saliva are likely to influence the behavior of ENMs in the oral cavity, but how the protein corona formed on the ENMs will alter bioavailability, or interact with the structure and proteins of the pellicle layer, as well as microbes in the biofilm, remains unclear. The tooth enamel is a dense crystalline structure that is likely to act as a barrier to ENM penetration, but underlying dentinal tubules are not. Consequently, ENMs may be used to strengthen dentine or regenerate pulp tissue. ENMs have dental applications as antibacterials for infection control, as nanofillers to improve the mechanical and bioactive properties of restoration materials, and as novel coatings on dental implants. Dentifrices and some related personal care products are already available for oral health applications. Overall, the clinical benefits generally outweigh the hazards of using ENMs in the oral cavity, and the latter should not prevent the responsible innovation of nanotechnology in dentistry. However, the clinical safety regulations for dental materials have not been specifically updated for ENMs, and some guidance on occupational health for practitioners is also needed. Knowledge gaps for future research include the formation of protein corona in the oral cavity, ENM diffusion through clinically relevant biofilms, and mechanistic investigations on how ENMs strengthen the tooth structure.

A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis.

PubMed

Naidoo, Anushka; Naidoo, Kogieleum; McIlleron, Helen; Essack, Sabiha; Padayatchi, Nesri

2017-11-01

Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens. © 2017, The American College of Clinical Pharmacology.

Overview on Clinical Relevance of Intra-Tumor Heterogeneity.

PubMed

Stanta, Giorgio; Bonin, Serena

2018-01-01

Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. In particular, intra-tumor heterogeneity (ITH) is closely related to cancer progression, resistance to therapy, and recurrences. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. This review tries to describe all the types of ITH including morphohistological ITH, and at the molecular level clonal ITH derived from genomic instability and nonclonal ITH derived from microenvironment interaction. It is important to consider the different types of ITH as a whole for any patient to investigate on cancer progression, prognosis, and treatment opportunities. From a practical point of view, analytical methods that are widely accessible today, or will be in the near future, are evaluated to investigate the complex pattern of ITH in a reproducible way for a clinical application.

Computerized clinical decision support for prescribing: provision does not guarantee uptake

PubMed Central

Moxey, Annette; Robertson, Jane; Newby, David; Hains, Isla; Williamson, Margaret; Pearson, Sallie-Anne

2010-01-01

There is wide variability in the use and adoption of recommendations generated by computerized clinical decision support systems (CDSSs) despite the benefits they may bring to clinical practice. We conducted a systematic review to explore the barriers to, and facilitators of, CDSS uptake by physicians to guide prescribing decisions. We identified 58 studies by searching electronic databases (1990–2007). Factors impacting on CDSS use included: the availability of hardware, technical support and training; integration of the system into workflows; and the relevance and timeliness of the clinical messages. Further, systems that were endorsed by colleagues, minimized perceived threats to professional autonomy, and did not compromise doctor-patient interactions were accepted by users. Despite advances in technology and CDSS sophistication, most factors were consistently reported over time and across ambulatory and institutional settings. Such factors must be addressed when deploying CDSSs so that improvements in uptake, practice and patient outcomes may be achieved. PMID:20064798

Prescription Drug Monitoring Programs: Ethical Issues in the Emergency Department.

PubMed

Marco, Catherine A; Venkat, Arvind; Baker, Eileen F; Jesus, John E; Geiderman, Joel M

2016-11-01

Prescription drug monitoring programs are statewide databases available to clinicians to track prescriptions of controlled medications. These programs may provide valuable information to assess the history and use of controlled substances and contribute to clinical decisionmaking in the emergency department (ED). The widespread availability of the programs raises important ethical issues about beneficence, nonmaleficence, respect for persons, justice, confidentiality, veracity, and physician autonomy. In this article, we review the ethical issues surrounding prescription drug monitoring programs and how those issues might be addressed to ensure the proper application of this tool in the ED. Clinical decisionmaking in regard to the appropriate use of opioids and other controlled substances is complex and should take into account all relevant clinical factors, including age, sex, clinical condition, medical history, medication history and potential drug-drug interactions, history of addiction or diversion, and disease state. Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

Capturing Essential Information to Achieve Safe Interoperability

PubMed Central

Weininger, Sandy; Jaffe, Michael B.; Rausch, Tracy; Goldman, Julian M.

2016-01-01

In this article we describe the role of “clinical scenario” information to assure the safety of interoperable systems, as well as the system’s ability to deliver the requisite clinical functionality to improve clinical care. Described are methods and rationale for capturing the clinical needs, workflow, hazards, and device interactions in the clinical environment. Key user (clinician and clinical engineer) needs and system requirements can be derived from this information, therefore improving the communication from clinicians to medical device and information technology system developers. This methodology is intended to assist the health care community, including researchers, standards developers, regulators, and manufacturers, by providing clinical definition to support requirements in the systems engineering process, particularly those focusing on development of Integrated Clinical Environments described in standard ASTM F2761. Our focus is on identifying and documenting relevant interactions and medical device capabilities within the system using a documentation tool called medical device interface data sheets (MDIDSa) and mitigating hazardous situations related to workflow, product usability, data integration, and the lack of effective medical device-health information technology system integration to achieve safe interoperability. Portions of the analysis of a clinical scenario for a “Patient-controlled analgesia safety interlock” are provided to illustrate the method. Collecting better clinical adverse event information and proposed solutions can help identify opportunities to improve current device capabilities and interoperability and support a Learning Health System to improve health care delivery. Developing and analyzing clinical scenarios are the first steps in creating solutions to address vexing patient safety problems and enable clinical innovation. A web-based research tool for implementing a means of acquiring and managing this information, the Clinical Scenario Repository™, is described. PMID:27387840

Capturing Essential Information to Achieve Safe Interoperability.

PubMed

Weininger, Sandy; Jaffe, Michael B; Rausch, Tracy; Goldman, Julian M

2017-01-01

In this article, we describe the role of "clinical scenario" information to assure the safety of interoperable systems, as well as the system's ability to deliver the requisite clinical functionality to improve clinical care. Described are methods and rationale for capturing the clinical needs, workflow, hazards, and device interactions in the clinical environment. Key user (clinician and clinical engineer) needs and system requirements can be derived from this information, therefore, improving the communication from clinicians to medical device and information technology system developers. This methodology is intended to assist the health care community, including researchers, standards developers, regulators, and manufacturers, by providing clinical definition to support requirements in the systems engineering process, particularly those focusing on development of Integrated Clinical Environments described in standard ASTM F2761. Our focus is on identifying and documenting relevant interactions and medical device capabilities within the system using a documentation tool called medical device interface data sheets and mitigating hazardous situations related to workflow, product usability, data integration, and the lack of effective medical device-health information technology system integration to achieve safe interoperability. Portions of the analysis of a clinical scenario for a "patient-controlled analgesia safety interlock" are provided to illustrate the method. Collecting better clinical adverse event information and proposed solutions can help identify opportunities to improve current device capabilities and interoperability and support a learning health system to improve health care delivery. Developing and analyzing clinical scenarios are the first steps in creating solutions to address vexing patient safety problems and enable clinical innovation. A Web-based research tool for implementing a means of acquiring and managing this information, the Clinical Scenario Repository™ (MD PnP Program), is described.

Cyclosporine in veterinary dermatology.

PubMed

Palmeiro, Brian S

2013-01-01

Cyclosporine is an immunomodulatory medication that is efficacious and approved for atopic dermatitis in dogs and allergic dermatitis in cats; it has also been used to successfully manage a variety of immune-mediated dermatoses in dogs and cats. This article reviews the use of cyclosporine in veterinary dermatology including its mechanism of action, pharmacokinetics, drug interactions, side effects, and relevant clinical updates. Dermatologic indications including atopic/allergic dermatitis, perianal fistulas, sebaceous adenitis, and other immune-mediated skin diseases are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Modeling the interaction between the intra-aortic balloon pump and the cardiovascular system: the effect of timing.

PubMed

Schampaert, Stéphanie; Rutten, Marcel C M; van T Veer, Marcel; van Nunen, Lokien X; Tonino, Pim A L; Pijls, Nico H J; van de Vosse, Frans N

2013-01-01

Because of the large number of interaction factors involved, the effects of the intra-aortic balloon pump (IABP) have not been investigated deeply. To enhance its clinical efficiency and to better define indications for use, advanced models are required to test the interaction between the IABP and the cardiovascular system. A patient with mild blood pressure depression and a lowered cardiac output is modeled in a lumped parameter computational model, developed with physiologically representative elements for relevant components of circulation and device. IABP support is applied, and the moments of balloon inflation and deflation are varied around their conventional timing modes. For validation purposes, timing is adapted within acceptable ranges in ten patients undergoing IABP therapy for typical clinical indications. In both model and patients, the IABP induces a diastolic blood pressure augmentation as well as a systolic reduction in afterload. The support capabilities of the IABP benefit the most when the balloon is deflated simultaneously with ventricular contraction, whereas inflation before onset of diastole unconditionally interferes with ejection. The physiologic response makes the model an excellent tool for testing the interaction between the IABP and the cardiovascular system, and how alterations of specific IABP parameters (i.e., timing) affect this coupling.

An analysis of contextual information relevant to medical care unexpectedly volunteered to researchers by asthma patients.

PubMed

Black, Heather L; Priolo, Chantel; Gonzalez, Rodalyn; Geer, Sabrina; Adam, Bariituu; Apter, Andrea J

2012-09-01

To describe and categorize contextual information relevant to patients' medical care unexpectedly volunteered to research personnel as part of a patient advocate (PA) intervention to facilitate access health care, communication with medical personnel, and self-management of a chronic disease such as asthma. We adapted a patient navigator intervention, to overcome barriers to access and communication for adults with moderate or severe asthma. Informed by focus groups of patients and providers, our PAs facilitated preparation for a visit with an asthma provider, attended the visit, confirmed understanding, and assisted with post-visit activities. During meetings with researchers, either for PA activities or for data collection, participants frequently volunteered personal and medical information relevant for achieving successful self-management that was not routinely shared with medical personnel. For this project, researchers journaled information not captured by the structured questionnaires and protocol. Using a qualitative analysis, we describe (1) researchers' journals of these unique communications; (2) their relevance for accomplishing self-management; (3) PAs' formal activities including teach-back, advocacy, and facilitating appointment making; and (4) observations of patients' interactions with the clinical practices. In 83 journals, patients' social support (83%), health (68%), and deportment (69%) were described. PA assistance with navigating the medical system (59%), teach-back (46%), and observed interactions with patient and medical staff (76%) were also journaled. Implicit were ways patients and practices could overcome barriers to access and communication. These journals describe the importance of seeking contextual and medically relevant information from all patients and, especially, those with significant morbidities, prompting patients for barriers to access to health care, and confirming understanding of medical information.

An analysis of contextual information relevant to medical care unexpectedly volunteered to researchers by asthma patients

PubMed Central

Black, Heather L.; Priolo, Chantel; Gonzalez, Rodalyn; Geer, Sabrina; Adam, Bariituu; Apter, Andrea J.

2012-01-01

Objective To describe and categorize contextual information relevant to patients’ medical care unexpectedly volunteered to research personnel as part of a patient advocate intervention to facilitate access health care, communication with medical personnel, and self-management of a chronic disease like asthma. Methods We adapted a patient navigator intervention, to overcome barriers to access and communication for adults with moderate or severe asthma. Informed by focus groups of patients and providers, our Patient Advocates facilitated preparation for a visit with an asthma provider, attended the visit, confirmed understanding, and assisted with post-visit activities. During meetings with researchers, either for PA activities or data collection, participants frequently volunteered personal and medical information relevant for achieving successful self-management that was not routinely shared with medical personnel. For this project, researchers journaled information not captured by the structured questionnaires and protocol. Using a qualitative analysis, we describe 1) researchers’ journals of these unique communications, 2) their relevance for accomplishing self-management, 3) Patient Advocates’ formal activities including teach-back, advocacy, and facilitating appointment-making, and 4) observations of patients’ interactions with the clinical practices. Results In 83 journals, patients’ social support (83%), health (68%), and deportment (69%) were described. Patient Advocate assistance with navigating the medical system (59%), teach-back (46%), and observed interactions with patient and medical staff (76%) were also journaled. Implicit were ways patients and practices could overcome barriers to access and communication. Conclusions These journals describe the importance of seeking contextual and medically relevant information from all patients and especially those with significant morbidities, prompting patients for barriers to accessing care, and confirming understanding of medical information. PMID:22788543

A survey of attitudes, practices, and knowledge regarding drug-drug interactions among medical residents in Iran.

PubMed

Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

2017-06-01

Background When prescribing medications, physicians should recognize clinically relevant potential drug-drug interactions (DDIs). To improve medication safety, it is important to understand prescribers' knowledge and opinions pertaining to DDIs. Objective To determine the current DDI information sources used by medical residents, their knowledge of DDIs, their opinions about performance feedback on co-prescription of interacting drugs. Setting Academic hospitals of Mashhad University of Medical Sciences (MUMS) in Iran. Methods A questionnaire containing questions regarding demographic and practice characteristics, DDI information sources, ability to recognize DDIs, and opinions about performance feedback was distributed to medical residents of 22 specialties in eight academic hospitals in Iran. We analyzed their perception pertaining to DDIs, their performance on classifying drug pairs, and we used a linear regression model to assess the association of potential determinants on their DDI knowledge. Main Outcome Measure prescribers' knowledge and opinions pertaining to DDIs. Results The overall response rate and completion rate for 315 distributed questionnaires were 90% (n = 295) and 86% (n = 281), respectively. Among DDI information sources, books, software on mobile phone or tablet, and Internet were the most commonly-used references. Residents could correctly classify only 41% (5.7/14) of the drug pairs. The regression model showed no significant association between residents' characteristics and their DDI knowledge. An overwhelming majority of the respondents (n = 268, 95.4%) wished to receive performance feedback on co-prescription of interacting drugs in their prescriptions. They mostly selected information technology-based tools (i.e. short text message and email) as their preferred method of receiving feedback. Conclusion Our findings indicate that prescribers may have poor ability to prevent clinically relevant potential DDI occurrence, and they perceive the need for performance feedback. These findings underline the importance of well-designed computerized alerting systems and delivering performance feedback to improve patient safety.

Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro.

PubMed

Germain, M A; Hatton, A; Williams, S; Matthews, J B; Stone, M H; Fisher, J; Ingham, E

2003-02-01

Concern over polyethylene wear particle induced aseptic loosening of metal-on-polyethylene hip prostheses has led to renewed interest in alternative materials such as metal-on-metal and alumina ceramic-on-alumina ceramic for total hip replacement. This study compared the effects of clinically relevant cobalt-chromium and alumina ceramic wear particles on the viability of U937 histiocytes and L929 fibroblasts in vitro. Clinically relevant cobalt-chromium wear particles were generated using a flat pin-on-plate tribometer. The mean size of the clinically relevant metal particles was 29.5+/-6.3 nm (range 5-200 nm). Clinically relevant alumina ceramic particles were generated in the Leeds MkII anatomical hip simulator from a Mittelmieier prosthesis using micro-separation motion. This produced particles with a bimodal size distribution. The majority (98%) of the clinically relevant alumina ceramic wear debris was 5-20 nm in size. The cytotoxicity of the clinically relevant wear particles was compared to commercially available cobalt-chromium (9.87 microm+/-5.67) and alumina ceramic (0.503+/-0.19 microm) particles. The effects of the particles on the cells over a 5 day period at different particle volume (microm(3)) to cell number ratios were tested and viability determined using ATP-Lite(TM). Clinically relevant cobalt-chromium particles 50 and 5 microm(3) per cell reduced the viability of U937 cells by 97% and 42% and reduced the viability of L929 cells by 95% and 73%, respectively. At 50 microm(3) per cell, the clinically relevant ceramic particles reduced U937 cell viability by 18%. None of the other concentrations of the clinically relevant particles were toxic. The commercial cobalt-chromium and alumina particles did not affect the viability of either the U937 histiocytes or the L929 fibroblasts.Thus at equivalent particle volumes the clinically relevant cobalt-chromium particles were more toxic then the alumina ceramic particles. This study has emphasised the fact that the nature, size and volume of particles are important in assessing biological effects of wear debris on cells in vitro.

Using video-annotation software to identify interactions in group therapies for schizophrenia: assessing reliability and associations with outcomes.

PubMed

Orfanos, Stavros; Akther, Syeda Ferhana; Abdul-Basit, Muhammad; McCabe, Rosemarie; Priebe, Stefan

2017-02-10

Research has shown that interactions in group therapies for people with schizophrenia are associated with a reduction in negative symptoms. However, it is unclear which specific interactions in groups are linked with these improvements. The aims of this exploratory study were to i) develop and test the reliability of using video-annotation software to measure interactions in group therapies in schizophrenia and ii) explore the relationship between interactions in group therapies for schizophrenia with clinically relevant changes in negative symptoms. Video-annotation software was used to annotate interactions from participants selected across nine video-recorded out-patient therapy groups (N = 81). Using the Individual Group Member Interpersonal Process Scale, interactions were coded from participants who demonstrated either a clinically significant improvement (N = 9) or no change (N = 8) in negative symptoms at the end of therapy. Interactions were measured from the first and last sessions of attendance (>25 h of therapy). Inter-rater reliability between two independent raters was measured. Binary logistic regression analysis was used to explore the association between the frequency of interactive behaviors and changes in negative symptoms, assessed using the Positive and Negative Syndrome Scale. Of the 1275 statements that were annotated using ELAN, 1191 (93%) had sufficient audio and visual quality to be coded using the Individual Group Member Interpersonal Process Scale. Rater-agreement was high across all interaction categories (>95% average agreement). A higher frequency of self-initiated statements measured in the first session was associated with improvements in negative symptoms. The frequency of questions and giving advice measured in the first session of attendance was associated with improvements in negative symptoms; although this was only a trend. Video-annotation software can be used to reliably identify interactive behaviors in groups for schizophrenia. The results suggest that proactive communicative gestures, as assessed by the video-analysis, predict outcomes. Future research should use this novel method in larger and clinically different samples to explore which aspects of therapy facilitate such proactive communication early on in therapy.

HEMORHEOLOGICAL IMPLICATIONS OF PERFLUOROCARBON BASED OXYGEN CARRIER INTERACTION WITH COLLOID PLASMA EXPANDERS AND BLOOD

PubMed Central

Vásquez, Diana M.; Ortiz, Daniel; Alvarez, Oscar A.; Briceño, Juan C.; Cabrales, Pedro

2013-01-01

Perfluorocarbon (PFC) emulsion based oxygen carriers lack colloid osmotic pressure (COP) and must be administered with colloid-based plasma expanders (PEs). Although PFC emulsions have been widely studied, there is limited information about PFC emulsion interaction with PEs and blood. Their interaction forms aggregates due to electrostatic and rheological phenomena, and change blood rheology and blood flow. This study analyzes the effects of the interaction between PFC emulsions with blood in the presence of clinically-used PEs. The rheological behavior of the mixtures was analyzed in parallel with in vivo analysis of blood flow in microvessels using intravital microscopy when administered in a clinically relevant scenario. The interaction between the PFC emulsion and PE with blood produced PFC droplets and red blood cell (RBCs) aggregation, and increased blood viscosity. The PFC droplets formed aggregates when mixed with PEs containing electrolytes, and the aggregation increased with the electrolyte concentration. Mixtures of PFC with PEs that produced PFC aggregates also induced RCBs aggregation when mixed with blood, increasing blood viscosity at low shear rates. The more viscous suspension at low shear rates produced a blunted blood flow velocity profile in vivo relative to non-aggregating mixtures of PFC and PEs. For the PEs evaluated, albumin produced minimal to undetectable aggregation. PFC and PEs interaction with blood can affect sections of the microcirculation with low shear rate (e.g. arterioles, venules, and pulmonary circulation) because aggregates could cause capillary occlusion, decrease perfusion, pulmonary emboli, or focal ischemia. PMID:23606592

Facilitating interprofessional evidence-based practice in paediatric rehabilitation: development, implementation and evaluation of an online toolkit for health professionals.

PubMed

Glegg, Stephanie M N; Livingstone, Roslyn; Montgomery, Ivonne

2016-01-01

Lack of time, competencies, resources and supports are documented as barriers to evidence-based practice (EBP). This paper introduces a recently developed web-based toolkit designed to assist interprofessional clinicians in implementing EBP within a paediatric rehabilitation setting. EBP theory, models, frameworks and tools were applied or adapted in the development of the online resources, which formed the basis of a larger support strategy incorporating interactive workshops, knowledge broker facilitation and mentoring. The highly accessed toolkit contains flowcharts with embedded information sheets, resources and templates to streamline, quantify and document outcomes throughout the EBP process. Case examples relevance to occupational therapy and physical therapy highlight the utility and application of the toolkit in a clinical paediatric setting. Workshops were highly rated by learners for clinical relevance, presentation level and effectiveness. Eight evidence syntheses have been created and 79 interventions have been evaluated since the strategy's inception in January 2011. The toolkit resources streamlined and supported EBP processes, promoting consistency in quality and presentation of outputs. The online toolkit can be a useful tool to facilitate clinicians' use of EBP in order to meet the needs of the clients and families whom they support. Implications for Rehabilitation A comprehensive online EBP toolkit for interprofessional clinicians is available to streamline the EBP process and to support learning needs regardless of competency level. Multi-method facilitation support, including interactive education, e-learning, clinical librarian services and knowledge brokering, is a valued but cost-restrictive supplement to the implementation of online EBP resources. EBP resources are not one-size-fits-all; targeted appraisal tools, models and frameworks may be integrated to improve their utility for specific sectors, which may limit them for others.

Recommendations for selecting drug-drug interactions for clinical decision support.

PubMed

Tilson, Hugh; Hines, Lisa E; McEvoy, Gerald; Weinstein, David M; Hansten, Philip D; Matuszewski, Karl; le Comte, Marianne; Higby-Baker, Stefanie; Hanlon, Joseph T; Pezzullo, Lynn; Vieson, Kathleen; Helwig, Amy L; Huang, Shiew-Mei; Perre, Anthony; Bates, David W; Poikonen, John; Wittie, Michael A; Grizzle, Amy J; Brown, Mary; Malone, Daniel C

2016-04-15

Recommendations for including drug-drug interactions (DDIs) in clinical decision support (CDS) are presented. A conference series was conducted to improve CDS for DDIs. A work group consisting of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information vendors, and healthcare organizations was convened to address (1) the process to use for developing and maintaining a standard set of DDIs, (2) the information that should be included in a knowledge base of standard DDIs, (3) whether a list of contraindicated drug pairs can or should be established, and (4) how to more intelligently filter DDI alerts. We recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated and more research to identify methods to safely reduce repetitive and less-relevant alerts. An expert panel with a centralized organizer or convener should be established to develop and maintain a standard set of DDIs for CDS in the United States. The process should be evidence driven, transparent, and systematic, with feedback from multiple stakeholders for continuous improvement. The scope of the expert panel's work should be carefully managed to ensure that the process is sustainable. Support for research to improve DDI alerting in the future is also needed. Adoption of these steps may lead to consistent and clinically relevant content for interruptive DDIs, thus reducing alert fatigue and improving patient safety. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation.

PubMed

Sabo, John P; Kort, Jens; Ballow, Charles; Kashuba, Angela D M; Haschke, Manuel; Battegay, Manuel; Girlich, Birgit; Ting, Naitee; Lang, Benjamin; Zhang, Wei; Cooper, Curtis; O'Brien, Drané; Seibert, Eleanore; Chan, Tom S; Tweedie, Donald; Li, Yongmei

2015-04-01

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms. © 2015, The American College of Clinical Pharmacology.

Liver Cytochrome P450 3A Ubiquitination in Vivo by gp78/Autocrine Motility Factor Receptor and C Terminus of Hsp70-interacting Protein (CHIP) E3 Ubiquitin Ligases

PubMed Central

Kim, Sung-Mi; Acharya, Poulomi; Engel, Juan C.; Correia, Maria Almira

2010-01-01

CYP3A4 is a dominant human liver cytochrome P450 enzyme engaged in the metabolism and disposition of >50% of clinically relevant drugs and held responsible for many adverse drug-drug interactions. CYP3A4 and its mammalian liver CYP3A orthologs are endoplasmic reticulum (ER)-anchored monotopic proteins that undergo ubiquitin (Ub)-dependent proteasomal degradation (UPD) in an ER-associated degradation (ERAD) process. These integral ER proteins are ubiquitinated in vivo, and in vitro studies have identified the ER-integral gp78 and the cytosolic co-chaperone, CHIP (C terminus of Hsp70-interacting protein), as the relevant E3 Ub-ligases, along with their cognate E2 Ub-conjugating enzymes UBC7 and UbcH5a, respectively. Using lentiviral shRNA templates targeted against each of these Ub-ligases, we now document that both E3s are indeed physiologically involved in CYP3A ERAD/UPD in cultured rat hepatocytes. Accordingly, specific RNAi resulted in ≈80% knockdown of each hepatic Ub-ligase, with a corresponding ≈2.5-fold CYP3A stabilization. Surprisingly, however, such stabilization resulted in increased levels of functionally active CYP3A, thereby challenging the previous notion that E3 recognition and subsequent ERAD of CYP3A proteins required ab initio their structural and/or functional inactivation. Furthermore, coexpression in HepG2 cells of both CYP3A4 and gp78, but not its functionally inactive RING-finger mutant, resulted in enhanced CYP3A4 loss greater than that in corresponding cells expressing only CYP3A4. Stabilization of a functionally active CYP3A after RNAi knockdown of either of the E3s, coupled with the increased CYP3A4 loss on gp78 or CHIP coexpression, suggests that ERAD-associated E3 Ub-ligases can influence clinically relevant drug metabolism by effectively regulating the physiological CYP3A content and consequently its function. PMID:20819951

Caregiver person-centeredness and behavioral symptoms during mealtime interactions: development and feasibility of a coding scheme.

PubMed

Gilmore-Bykovskyi, Andrea L

2015-01-01

Mealtime behavioral symptoms are distressing and frequently interrupt eating for the individual experiencing them and others in the environment. A computer-assisted coding scheme was developed to measure caregiver person-centeredness and behavioral symptoms for nursing home residents with dementia during mealtime interactions. The purpose of this pilot study was to determine the feasibility, ease of use, and inter-observer reliability of the coding scheme, and to explore the clinical utility of the coding scheme. Trained observers coded 22 observations. Data collection procedures were acceptable to participants. Overall, the coding scheme proved to be feasible, easy to execute and yielded good to very good inter-observer agreement following observer re-training. The coding scheme captured clinically relevant, modifiable antecedents to mealtime behavioral symptoms, but would be enhanced by the inclusion of measures for resident engagement and consolidation of items for measuring caregiver person-centeredness that co-occurred and were difficult for observers to distinguish. Published by Elsevier Inc.

Education in the workplace for the physician: clinical management states as an organizing framework.

PubMed

Greenes, R A

2000-01-01

Medical educators are interested in approaches to making selected relevant knowledge available in the context of problem-based care. This is of value both during the process of care and as a means of organizing information for offline self-study. Four trends in health information technology are relevant to achieving the goal and can be expected to play a growing role in the future. First, health care enterprises are developing approaches for access to information resources related to the care of a patient, including clinical data and images but also communication tools, referral and other logistic tools, decision support, and educational materials. Second, information for patients and methods for patient-doctor interaction and decision making are becoming available. Third, computer-based methods for representation of practice guidelines are being developed to support applications that can incorporate their logic. Finally, considering patients as being in particular "clinical management states" (or CMSs) for specific problems, approaches are being developed to use guidelines as a kind of "predictive" framework to enable development of interfaces for problem-based clinical encounters. The guidelines for a CMS can be used to identify the kinds of resources specifically needed for clinical encounters of that type. As the above trends converge to produce problem-specific environments, professional specialty organizations and continuing medical education course designers will need to focus energies on organizing and updating medical knowledge to make it available in CMS-specific contexts.

Robot-supported assessment of balance in standing and walking.

PubMed

Shirota, Camila; van Asseldonk, Edwin; Matjačić, Zlatko; Vallery, Heike; Barralon, Pierre; Maggioni, Serena; Buurke, Jaap H; Veneman, Jan F

2017-08-14

Clinically useful and efficient assessment of balance during standing and walking is especially challenging in patients with neurological disorders. However, rehabilitation robots could facilitate assessment procedures and improve their clinical value. We present a short overview of balance assessment in clinical practice and in posturography. Based on this overview, we evaluate the potential use of robotic tools for such assessment. The novelty and assumed main benefits of using robots for assessment are their ability to assess 'severely affected' patients by providing assistance-as-needed, as well as to provide consistent perturbations during standing and walking while measuring the patient's reactions. We provide a classification of robotic devices on three aspects relevant to their potential application for balance assessment: 1) how the device interacts with the body, 2) in what sense the device is mobile, and 3) on what surface the person stands or walks when using the device. As examples, nine types of robotic devices are described, classified and evaluated for their suitability for balance assessment. Two example cases of robotic assessments based on perturbations during walking are presented. We conclude that robotic devices are promising and can become useful and relevant tools for assessment of balance in patients with neurological disorders, both in research and in clinical use. Robotic assessment holds the promise to provide increasingly detailed assessment that allows to individually tailor rehabilitation training, which may eventually improve training effectiveness.

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Separate and interactive contributions of weak inhibitory control and threat sensitivity to prediction of suicide risk.

PubMed

Venables, Noah C; Sellbom, Martin; Sourander, Andre; Kendler, Kenneth S; Joiner, Thomas E; Drislane, Laura E; Sillanmäki, Lauri; Elonheimo, Henrik; Parkkola, Kai; Multimaki, Petteri; Patrick, Christopher J

2015-04-30

Biobehavioral dispositions can serve as valuable referents for biologically oriented research on core processes with relevance to many psychiatric conditions. The present study examined two such dispositional variables-weak response inhibition (or disinhibition; INH-) and threat sensitivity (or fearfulness; THT+)-as predictors of the serious transdiagnostic problem of suicide risk in two samples: male and female outpatients from a U.S. clinic (N=1078), and a population-based male military cohort from Finland (N=3855). INH- and THT+ were operationalized through scores on scale measures of disinhibition and fear/fearlessness, known to be related to DSM-defined clinical conditions and brain biomarkers. Suicide risk was assessed by clinician ratings (clinic sample) and questionnaires (both samples). Across samples and alternative suicide indices, INH- and THT+ each contributed uniquely to prediction of suicide risk-beyond internalizing and externalizing problems in the case of the clinic sample where diagnostic data were available. Further, in both samples, INH- and THT+ interactively predicted suicide risk, with individuals scoring concurrently high on both dispositions exhibiting markedly augmented risk. Findings demonstrate that dispositional constructs of INH- and THT+ are predictive of suicide risk, and hold potential as referents for biological research on suicidal behavior. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Understanding the optimal learning environment in palliative care.

PubMed

Connell, Shirley E; Yates, Patsy; Barrett, Linda

2011-07-01

The learning experiences of student nurses undertaking clinical placement are reported widely, however little is known about the learning experiences of health professionals undertaking continuing professional development (CPD) in a clinical setting, especially in palliative care. The aim of this study, which was conducted as part of the national evaluation of a professional development program involving clinical attachments with palliative care services (The Program of Experience in the Palliative Approach [PEPA]), was to explore factors influencing the learning experiences of participants over time. Thirteen semi-structured, one-to-one telephone interviews were conducted with five participants throughout their PEPA experience. The analysis was informed by the traditions of adult, social and psychological learning theories and relevant literature. The participants' learning was enhanced by engaging interactively with host site staff and patients, and by the validation of their personal and professional life experiences together with the reciprocation of their knowledge with host site staff. Self-directed learning strategies maximised the participants' learning outcomes. Inclusion in team activities aided the participants to feel accepted within the host site. Personal interactions with host site staff and patients shaped this social/cultural environment of the host site. Optimal learning was promoted when participants were actively engaged, felt accepted and supported by, and experienced positive interpersonal interactions with, the host site staff. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fgf8 expression in the Tbx1 domain causes skeletal abnormalities and modifies the aortic arch but not the outflow tract phenotype of Tbx1 mutants

PubMed Central

Vitelli, Francesca; Zhang, Zhen; Huynh, Tuong; Sobotka, Angela; Mupo, Annalisa; Baldini, Antonio

2007-01-01

Fgf8 and Tbx1 have been shown to interact in patterning the aortic arch, and both genes are required in formation and growth of the outflow tract of the heart. However, the nature of the interaction of the two genes is unclear. We have utilized a novel Tbx1Fgf8 allele which drives Fgf8 expression in Tbx1-positive cells and an inducible Cre-LoxP recombination system to address the role of Fgf8 in Tbx1 positive cells in modulating cardiovascular development. Results support a requirement of Fgf8 in Tbx1 expressing cells to finely control patterning of the aortic arch and great arteries specifically during the pharyngeal arch artery remodeling process and indicate that the endoderm is the most likely site of this interaction. Furthermore, our data suggest that Fgf8 and Tbx1 play independent roles in regulating outflow tract development. This finding is clinically relevant since TBX1 is the candidate for DGS/VCFS, characterized clinically by variable expressivity and reduced penetrance of cardiovascular defects; Fgf8 gene variants may provide molecular clues to this variability. PMID:16696966

Caregiver Person-Centeredness and Behavioral Symptoms during Mealtime Interactions: Development and Feasibility of a Coding Scheme

PubMed Central

Gilmore-Bykovskyi, Andrea L.

2015-01-01

Mealtime behavioral symptoms are distressing and frequently interrupt eating for the individual experiencing them and others in the environment. In order to enable identification of potential antecedents to mealtime behavioral symptoms, a computer-assisted coding scheme was developed to measure caregiver person-centeredness and behavioral symptoms for nursing home residents with dementia during mealtime interactions. The purpose of this pilot study was to determine the acceptability and feasibility of procedures for video-capturing naturally-occurring mealtime interactions between caregivers and residents with dementia, to assess the feasibility, ease of use, and inter-observer reliability of the coding scheme, and to explore the clinical utility of the coding scheme. Trained observers coded 22 observations. Data collection procedures were feasible and acceptable to caregivers, residents and their legally authorized representatives. Overall, the coding scheme proved to be feasible, easy to execute and yielded good to very good inter-observer agreement following observer re-training. The coding scheme captured clinically relevant, modifiable antecedents to mealtime behavioral symptoms, but would be enhanced by the inclusion of measures for resident engagement and consolidation of items for measuring caregiver person-centeredness that co-occurred and were difficult for observers to distinguish. PMID:25784080

Recommended Approaches for Pharmacokinetic Natural Product-Drug Interaction Research: a NaPDI Center Commentary.

PubMed

Paine, Mary F; Shen, Danny D; McCune, Jeannine S

2018-05-07

Sales of botanical dietary supplements and other purported medicinal natural products (NPs) have escalated over the past ~25 years, increasing the potential for NPs to precipitate clinically significant pharmacokinetic interactions with United States Food and Drug Administration (FDA)-approved medications (NP-drug interactions or NPDIs). Published NPDI studies to date often lack consistency in design, implementation, and documentation, which present difficulties in assessing the clinical significance of the results. Common hurdles include large variability in the admixture composition of phytoconstituents between and within batches of a given NP, limited knowledge on the pharmacokinetics of precipitant NP constituents, and use of animal and/or in vitro models which, in some cases, are not mechanistically appropriate for extrapolation to humans. The National Center for Complementary and Integrative Health has created a Center of Excellence for Natural Product-Drug Interaction (NaPDI Center) to address these unmet research needs. The NaPDI Center has two overarching goals: 1) develop Recommended Approaches to guide researchers in the proper conduct of NPDI studies, which will evolve over time concurrent with emerging technologies and new research data; and 2) apply the Recommended Approaches in evaluating four model NPs as precipitants of NPDIs with clinically relevant object drugs. The major objectives of this commentary are to 1) explain the rationale for creating the NaPDI Center; 2) describe the Decision Trees developed by the NaPDI Center to enhance the planning, rigor, and consistency of NPDI studies; and 3) provide a framework for communicating results to the multidisciplinary scientists interested in the NaPDI Center&rsquo's Interaction Projects. The American Society for Pharmacology and Experimental Therapeutics.

CLINICAL AUTONOMIC NEUROPHYSIOLOGY AND THE MALE SEXUAL RESPONSE: AN OVERVIEW

PubMed Central

Yang, Claire C.; Jiang, Xiaogang

2009-01-01

Introduction Clinical neurophysiology is the study of the human nervous system through the recording of bioelectrical activity. In the realm of male sexual functioning, this includes using electrophysiologic techniques to study the nerves subserving erection, emission, ejaculation, and orgasm. Aim To introduce the reader to the principles of clinical neurophysiology as they relate to the male sexual response, particularly erection. Methods We review the pertinent autonomic neuroanatomy and neurophysiology of reflexes relevant to the male sexual response, as well as summarize the genital electrodiagnostic tests that are being used to interrogate the autonomic innervation pertinent to male sexual functioning. Conclusions The male sexual response is a coordinated series of interactions between the somatic and the autonomic nervous systems. Measurement of the autonomically mediated portions of the sexual reflexes is of great clinical interest, particularly in relation to erection. Advances in clinical electrodiagnostics now allow for consistent recording of evoked and spontaneous intra-penile electrical activity. However, before broad and widespread use of these techniques is possible, more investigations are needed. PMID:19267845

Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation.

PubMed

De Pablo, Carmen; Orden, Samuel; Apostolova, Nadezda; Blanquer, Amando; Esplugues, Juan V; Alvarez, Angeles

2010-06-01

Abacavir and didanosine are nucleoside reverse transcriptase inhibitors (NRTI) widely used in therapy for HIV-infection but which have been linked to cardiovascular complications. The objective of this study was to analyze the effects of clinically relevant doses of abacavir and didanosine on human leukocyte-endothelium interactions and to compare them with those of other NRTIs. The interactions between human leukocytes - specifically peripheral blood polymorphonuclear (PMN) or mononuclear (PBMC) cells - and human umbilical vein endothelial cells were evaluated in a flow chamber system that reproduces conditions in vivo. The expression of adhesion molecules was analyzed by flow cytometry. Abacavir induced a dose-dependent increase in PMN and PBMC rolling and adhesion. This was reproduced by didanosine but not by lamivudine or zidovudine. Both abacavir and didanosine increased Mac-1 expression in neutrophils and monocytes, but produced no effects on either lymphocytes or the expression of endothelial adhesion molecules. The PMN/PBMC rolling and adhesion induced by abacavir or didanosine did not occur when antibodies against Mac-1 or its ligand ICAM-1 were blocked. Abacavir induces significant human leukocyte accumulation through the activation of Mac-1, which in turn interacts with its endothelial ligand ICAM-1. The fact that didanosine exhibits similar effects and that lamivudine and zidovudine do not points to a relationship between the chemical structure of NRTIs and the induction of leukocyte/endothelial cell interactions. This mechanism may be especially relevant to the progression of the vascular damage associated with atherosclerosis and myocardial infarction in abacavir and didanosine-treated patients.

Privacy enhancing techniques - the key to secure communication and management of clinical and genomic data.

PubMed

De Moor, G J E; Claerhout, B; De Meyer, F

2003-01-01

To introduce some of the privacy protection problems related to genomics based medicine and to highlight the relevance of Trusted Third Parties (TTPs) and of Privacy Enhancing Techniques (PETs) in the restricted context of clinical research and statistics. Practical approaches based on two different pseudonymisation models, both for batch and interactive data collection and exchange, are described and analysed. The growing need of managing both clinical and genetic data raises important legal and ethical challenges. Protecting human rights in the realm of privacy, while optimising research potential and other statistical activities is a challenge that can easily be overcome with the assistance of a trust service provider offering advanced privacy enabling/enhancing solutions. As such, the use of pseudonymisation and other innovative Privacy Enhancing Techniques can unlock valuable data sources.

Animal to human translational paradigms relevant for approach avoidance conflict decision making.

PubMed

Kirlic, Namik; Young, Jared; Aupperle, Robin L

2017-09-01

Avoidance behavior in clinical anxiety disorders is often a decision made in response to approach-avoidance conflict, resulting in a sacrifice of potential rewards to avoid potential negative affective consequences. Animal research has a long history of relying on paradigms related to approach-avoidance conflict to model anxiety-relevant behavior. This approach includes punishment-based conflict, exploratory, and social interaction tasks. There has been a recent surge of interest in the translation of paradigms from animal to human, in efforts to increase generalization of findings and support the development of more effective mental health treatments. This article briefly reviews animal tests related to approach-avoidance conflict and results from lesion and pharmacologic studies utilizing these tests. We then provide a description of translational human paradigms that have been developed to tap into related constructs, summarizing behavioral and neuroimaging findings. Similarities and differences in findings from analogous animal and human paradigms are discussed. Lastly, we highlight opportunities for future research and paradigm development that will support the clinical utility of this translational work. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial).

PubMed

Bansilal, Sameer; Bloomgarden, Zachary; Halperin, Jonathan L; Hellkamp, Anne S; Lokhnygina, Yuliya; Patel, Manesh R; Becker, Richard C; Breithardt, Günter; Hacke, Werner; Hankey, Graeme J; Nessel, Christopher C; Singer, Daniel E; Berkowitz, Scott D; Piccini, Jonathan P; Mahaffey, Kenneth W; Fox, Keith A A

2015-10-01

The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

PubMed Central

2013-01-01

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

A CRISPR toolbox to study virus–host interactions

PubMed Central

Puschnik, Andreas S.; Majzoub, Karim; Ooi, Yaw Shin; Carette, Jan E.

2018-01-01

Viruses depend on their hosts to complete their replication cycles; they exploit cellular receptors for entry and hijack cellular functions to replicate their genome, assemble progeny virions and spread. Recently, genome-scale CRISPR–Cas screens have been used to identify host factors that are required for virus replication, including the replication of clinically relevant viruses such as Zika virus, West Nile virus, dengue virus and hepatitis C virus. In this Review, we discuss the technical aspects of genome-scale knockout screens using CRISPR–Cas technology, and we compare these screens with alternative genetic screening technologies. The relative ease of use and reproducibility of CRISPR–Cas make it a powerful tool for probing virus–host interactions and for identifying new antiviral targets. PMID:28420884

BIOPHYSICAL PROPERTIES OF NUCLEIC ACIDS AT SURFACES RELEVANT TO MICROARRAY PERFORMANCE.

PubMed

Rao, Archana N; Grainger, David W

2014-04-01

Both clinical and analytical metrics produced by microarray-based assay technology have recognized problems in reproducibility, reliability and analytical sensitivity. These issues are often attributed to poor understanding and control of nucleic acid behaviors and properties at solid-liquid interfaces. Nucleic acid hybridization, central to DNA and RNA microarray formats, depends on the properties and behaviors of single strand (ss) nucleic acids (e.g., probe oligomeric DNA) bound to surfaces. ssDNA's persistence length, radius of gyration, electrostatics, conformations on different surfaces and under various assay conditions, its chain flexibility and curvature, charging effects in ionic solutions, and fluorescent labeling all influence its physical chemistry and hybridization under assay conditions. Nucleic acid (e.g., both RNA and DNA) target interactions with immobilized ssDNA strands are highly impacted by these biophysical states. Furthermore, the kinetics, thermodynamics, and enthalpic and entropic contributions to DNA hybridization reflect global probe/target structures and interaction dynamics. Here we review several biophysical issues relevant to oligomeric nucleic acid molecular behaviors at surfaces and their influences on duplex formation that influence microarray assay performance. Correlation of biophysical aspects of single and double-stranded nucleic acids with their complexes in bulk solution is common. Such analysis at surfaces is not commonly reported, despite its importance to microarray assays. We seek to provide further insight into nucleic acid-surface challenges facing microarray diagnostic formats that have hindered their clinical adoption and compromise their research quality and value as genomics tools.

BIOPHYSICAL PROPERTIES OF NUCLEIC ACIDS AT SURFACES RELEVANT TO MICROARRAY PERFORMANCE

PubMed Central

Rao, Archana N.; Grainger, David W.

2014-01-01

Both clinical and analytical metrics produced by microarray-based assay technology have recognized problems in reproducibility, reliability and analytical sensitivity. These issues are often attributed to poor understanding and control of nucleic acid behaviors and properties at solid-liquid interfaces. Nucleic acid hybridization, central to DNA and RNA microarray formats, depends on the properties and behaviors of single strand (ss) nucleic acids (e.g., probe oligomeric DNA) bound to surfaces. ssDNA’s persistence length, radius of gyration, electrostatics, conformations on different surfaces and under various assay conditions, its chain flexibility and curvature, charging effects in ionic solutions, and fluorescent labeling all influence its physical chemistry and hybridization under assay conditions. Nucleic acid (e.g., both RNA and DNA) target interactions with immobilized ssDNA strands are highly impacted by these biophysical states. Furthermore, the kinetics, thermodynamics, and enthalpic and entropic contributions to DNA hybridization reflect global probe/target structures and interaction dynamics. Here we review several biophysical issues relevant to oligomeric nucleic acid molecular behaviors at surfaces and their influences on duplex formation that influence microarray assay performance. Correlation of biophysical aspects of single and double-stranded nucleic acids with their complexes in bulk solution is common. Such analysis at surfaces is not commonly reported, despite its importance to microarray assays. We seek to provide further insight into nucleic acid-surface challenges facing microarray diagnostic formats that have hindered their clinical adoption and compromise their research quality and value as genomics tools. PMID:24765522

Sporotrichosis between 1898 and 2017: The evolution of knowledge on a changeable disease and on emerging etiological agents.

PubMed

Lopes-Bezerra, Leila M; Mora-Montes, Hector M; Zhang, Yu; Nino-Vega, Gustavo; Rodrigues, Anderson Messias; de Camargo, Zoilo Pires; de Hoog, Sybren

2018-04-01

The description of cryptic species with different pathogenic potentials has changed the perspectives on sporotrichosis. Sporothrix schenckii causes a benign chronic subcutaneous mycosis, Sporothrix brasiliensis is highly virulent, and Sporothrix globosa mainly causes fixed cutaneous lesions. Furthermore, S. brasiliensis is the prevalent species related to cat-transmitted sporotrichosis. Sources of infection, transmission, and distribution patterns also differ between species, and variability differs between species because of different degrees of clonality. The present review article will cover several aspects of the biology of clinically relevant agents of sporotrichosis, including epidemiological aspects of emerging species. Genomic information of Sporothrix spp. is also discussed. The cell wall is an essential structure for cell viability, interaction with the environment, and the host immune cells and contains several macromolecules involved in virulence. Due to its importance, aspects of glycosylation and cell wall polysaccharides are reviewed. Recent genome data and bioinformatics analyses helped to identify specific enzymes of the biosynthetic glycosylation routes, with no homologs in mammalian cells, which can be putative targets for development of antifungal drugs. A diversity of molecular techniques is available for the recognition of the clinically relevant species of Sporothrix. Furthermore, antigens identified as diagnostic markers and putative vaccine candidates are described. Cell-mediated immunity plays a key role in controlling infection, but Sporothrix species differ in their interaction with the host. The adaptive branch of the immune response is essential for appropriate control of infection.

Gut microbiota and bacterial translocation in digestive surgery: the impact of probiotics.

PubMed

Komatsu, Shunichiro; Yokoyama, Yukihiro; Nagino, Masato

2017-05-01

It is conceivable that manipulation of the gut microbiota could reduce the incidence or magnitude of surgical complications in digestive surgery. However, the evidence remains inconclusive, although much effort has been devoted to randomized controlled trials (RCTs) and meta-analyses on probiotics. Furthermore, the mechanism behind the protective effects of probiotics appears elusive, our understanding of probiotic actions being fragmentary. The objective of this review is to assess the clinical relevance of the perioperative use of probiotics in major digestive surgery, based on a comprehensive view of the gut microbiota, bacterial translocation (BT), and host defense system. The first part of this article describes the pathophysiological events associated with the gut microbiota. Results of RCTs for the perioperative use of probiotics in major digestive surgery are reviewed in the latter part. The development of the structural and functional barrier to protect against BT primarily results from the generally cooperative interactions between the host and resident microbiota. There is a large body of evidence indicating that probiotics, by enhancing beneficial interactions, reinforce the host defense system to limit BT. The perioperative use of probiotics in patients undergoing hepatobiliary and pancreatic surgery is a promising approach for the prevention of postoperative infectious complications, while the effectiveness in colorectal surgery remains controversial due to substantial heterogeneity among the RCTs with small sample populations. Further studies, such as multi-center RCTs with a larger sample size, are necessary to confirm the clinical relevance of probiotic agents in major digestive surgery.

21 CFR 1271.75 - How do I screen a donor?

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... risk factors for and clinical evidence of relevant cell-associated communicable disease agents and... having either of the following: (1) A risk factor for or clinical evidence of any of the relevant...

Developing an interactive mobile phone self-report system for self-management of hypertension. Part 2: content validity and usability.

PubMed

Bengtsson, Ulrika; Kjellgren, Karin; Höfer, Stefan; Taft, Charles; Ring, Lena

2014-10-01

Self-management support tools using technology may improve adherence to hypertension treatment. There is a need for user-friendly tools facilitating patients' understanding of the interconnections between blood pressure, wellbeing and lifestyle. This study aimed to examine comprehension, comprehensiveness and relevance of items, and further to evaluate the usability and reliability of an interactive hypertension-specific mobile phone self-report system. Areas important in supporting self-management and candidate items were derived from five focus group interviews with patients and healthcare professionals (n = 27), supplemented by a literature review. Items and response formats were drafted to meet specifications for mobile phone administration and were integrated into a mobile phone data-capture system. Content validity and usability were assessed iteratively in four rounds of cognitive interviews with patients (n = 21) and healthcare professionals (n = 4). Reliability was examined using a test-retest. Focus group analyses yielded six areas covered by 16 items. The cognitive interviews showed satisfactory item comprehension, relevance and coverage; however, one item was added. The mobile phone self-report system was reliable and perceived easy to use. The mobile phone self-report system appears efficiently to capture information relevant in patients' self-management of hypertension. Future studies need to evaluate the effectiveness of this tool in improving self-management of hypertension in clinical practice.

An introductory orientation to clinical pathology core and on-call responsibilities.

PubMed

Pappas, A A; Drew, M J; Flick, J; Fink, L; Fuller, G L; Hough, A J

1994-05-01

An introductory 4-week orientation for clinical pathology is described. There were 76 hours of lectures, 74 hours of conferences, and 68 hours of laboratories for a total of 221 hours. During the orientation, all calls handled by the residents were evaluated as to resolution, patient outcome, and interaction required. Eighty calls were received during the orientation from 57 technologists (71%), 16 physicians (20%), and seven nurses (9%). The calls originated concerning the following: blood banking, 37 (46%); hematology, 21 (27%); chemistry, 14 (18%); microbiology, five (6%); and administration, three (4%). Sixty percent of the calls were consultative and 40% were supervisory. Ninety-nine percent were handled appropriately by the residents. Patient outcome was moderately or significantly affected in 44% of all calls, divided between 67% of all consultative calls and 9% of all supervisory calls. Significant pathologist interaction was required in 49% of all calls, divided between 71% of the consultative calls and 16% of the supervisory calls. Using this integrated, dynamic system of resident instruction, on-call experience, and evaluation, residents quickly gain confidence in handling call, didactic clinical consultation, and patient management. The orientation and on-call system described provides for a relevant and dynamic system for resident education.

Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure

PubMed Central

Damman, Kevin; A.E. Valente, Mattia; J. van Veldhuisen, Dirk; G.F. Cleland, John; M. O’Connor, Christopher; Metra, Marco; Ponikowski, Piotr; Cotter, Gad; Davison, Beth; M. Givertz, Michael; M. Bloomfield, Daniel; L. Hillege, Hans; A. Voors, Adriaan

2017-01-01

The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF. PMID:28698481

Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure.

PubMed

Damman, Kevin; Valente, Mattia A E; van Veldhuisen, Dirk J; Cleland, John G F; O'Connor, Christopher M; Metra, Marco; Ponikowski, Piotr; Cotter, Gad; Davison, Beth; Givertz, Michael M; Bloomfield, Daniel M; Hillege, Hans L; Voors, Adriaan A

2017-07-08

The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A₁Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization ( p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF ( p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF.

Influence of Food on Paediatric Gastrointestinal Drug Absorption Following Oral Administration: A Review

PubMed Central

Batchelor, Hannah K.

2015-01-01

The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations. PMID:27417362

In-vitro interaction of tafenoquine and chloroquine in Plasmodium falciparum from northwestern Thailand.

PubMed

Vollnberg, Anke; Prajakwong, Somsak; Sirichaisinthop, Jeeraphat; Wiedermann, Gerhard; Wernsdorfer, Gunther; Wernsdorfer, Walther H

2003-01-01

The blood schizontocidal, pharmacodynamic interaction between tafenoquine (WR 238605--a 5-phenoxyprimaquine derivative--and chloroquine was investigated, using an in-vitro test for the inhibition of schizont maturation, in 15 fresh isolates of Plasmodium falciparum that originated from northwestern Thailand and neighbouring Myanmar. In this area the parasite is highly resistant to chloroquine. The geometric mean cut-off concentrations of schizont maturation for tafenoquine and chloroquine were 5261 nM and 7638 nM, respectively. With a mixture of tafenoquine and chloroquine, the mean cut-off concentration was 5252 nM, corresponding to 389 nM tafenoquine + 4863 nM chloroquine. Further analysis showed that the interaction between tafenoquine and chloroquine was additive within the range of EC20 and EC77. At concentrations higher than the EC77, interaction was moderately synergistic. While tafenoquine did not reverse the resistance to chloroquine to the degree of clinically relevant sensitivity, there was evidence that the blood schizontocidal efficacy of tafenoquine would be enhanced in the presence of chloroquine.

Structural basis for the interaction of antibiotics with peptidyl transferase center in eubacteria

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

Schlunzen, Frank; Zarivach, Raz; Harms, Jörg

2009-10-07

Ribosomes, the site of protein synthesis, are a major target for natural and synthetic antibiotics. Detailed knowledge of antibiotic binding sites is central to understanding the mechanisms of drug action. Conversely, drugs are excellent tools for studying the ribosome function. To elucidate the structural basis of ribosome-antibiotic interactions, we determined the high-resolution X-ray structures of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans, complexed with the clinically relevant antibiotics chloramphenicol, clindamycin and the three macrolides erythromycin, clarithromycin and roxithromycin. We found that antibiotic binding sites are composed exclusively of segments of 23S ribosomal RNA at the peptidyl transferase cavitymore » and do not involve any interaction of the drugs with ribosomal proteins. Here we report the details of antibiotic interactions with the components of their binding sites. Our results also show the importance of putative Mg{sup +2} ions for the binding of some drugs. This structural analysis should facilitate rational drug design.« less

An internal thioester in a pathogen surface protein mediates covalent host binding

PubMed Central

Walden, Miriam; Edwards, John M; Dziewulska, Aleksandra M; Bergmann, Rene; Saalbach, Gerhard; Kan, Su-Yin; Miller, Ona K; Weckener, Miriam; Jackson, Rosemary J; Shirran, Sally L; Botting, Catherine H; Florence, Gordon J; Rohde, Manfred; Banfield, Mark J; Schwarz-Linek, Ulrich

2015-01-01

To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a ‘chemical harpoon’. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions. DOI: http://dx.doi.org/10.7554/eLife.06638.001 PMID:26032562

Live Attenuated Influenza Virus Increases Pneumococcal Translocation and Persistence Within the Middle Ear

PubMed Central

Mina, Michael J.; Klugman, Keith P.; Rosch, Jason W.; McCullers, Jonathan A.

2015-01-01

Background. Infection with influenza A virus (IAV) increases susceptibility to respiratory bacterial infections, resulting in increased bacterial carriage and complications such acute otitis media, pneumonia, bacteremia, and meningitis. Recently, vaccination with live attenuated influenza virus (LAIV) was reported to enhance subclinical bacterial colonization within the nasopharynx, similar to IAV. Although LAIV does not predispose to bacterial pneumonia, whether it may alter bacterial transmigration toward the middle ear, where it could have clinically relevant implications, has not been investigated. Methods. BALB/c mice received LAIV or phosphate-buffered saline 1 or 7 days before or during pneumococcal colonization with either of 2 clinical isolates, 19F or 7F. Middle ear bacterial titers were monitored daily via in vivo imaging. Results. LAIV increased bacterial transmigration to and persistence within the middle ear. When colonization followed LAIV inoculation, a minimum LAIV incubation period of 4 days was required before bacterial transmigration commenced. Conclusions. While LAIV vaccination is safe and effective at reducing IAV and coinfection with influenza virus and bacteria, LAIV may increase bacterial transmigration to the middle ear and could thus increase the risk of clinically relevant acute otitis media. These data warrant further investigations into interactions between live attenuated viruses and naturally colonizing bacterial pathogens. PMID:25505300

Concise Review: Microfluidic Technology Platforms: Poised to Accelerate Development and Translation of Stem Cell-Derived Therapies

PubMed Central

Titmarsh, Drew M.; Chen, Huaying; Glass, Nick R.; Cooper-White, Justin J.

2014-01-01

Stem cells are a powerful resource for producing a variety of cell types with utility in clinically associated applications, including preclinical drug screening and development, disease and developmental modeling, and regenerative medicine. Regardless of the type of stem cell, substantial barriers to clinical translation still exist and must be overcome to realize full clinical potential. These barriers span processes including cell isolation, expansion, and differentiation; purification, quality control, and therapeutic efficacy and safety; and the economic viability of bioprocesses for production of functional cell products. Microfluidic systems have been developed for a myriad of biological applications and have the intrinsic capability of controlling and interrogating the cellular microenvironment with unrivalled precision; therefore, they have particular relevance to overcoming such barriers to translation. Development of microfluidic technologies increasingly utilizes stem cells, addresses stem cell-relevant biological phenomena, and aligns capabilities with translational challenges and goals. In this concise review, we describe how microfluidic technologies can contribute to the translation of stem cell research outcomes, and we provide an update on innovative research efforts in this area. This timely convergence of stem cell translational challenges and microfluidic capabilities means that there is now an opportunity for both disciplines to benefit from increased interaction. PMID:24311699

Mobile phone interference with medical equipment and its clinical relevance: a systematic review.

PubMed

Lawrentschuk, Nathan; Bolton, Damien M

2004-08-02

To conduct a systematic review of studies on clinically relevant digital mobile phone electromagnetic interference with medical equipment. MEDLINE and SUMSEARCH were searched for the period 1966-2004. The Cochrane Library and Database of Abstracts of Reviews of Effects were also searched for systematic reviews. Studies were eligible if published in a peer-reviewed journal in English, and if they included testing of digital mobile phones for clinically relevant interference with medical equipment used to monitor or treat patients, but not implantable medical devices. As there was considerable heterogeneity in medical equipment studied and the conduct of testing, results were summarised rather than subjected to meta-analysis. Clinically relevant electromagnetic interference (EMI) secondary to mobile phones potentially endangering patients occurred in 45 of 479 devices tested at 900 MHz and 14 of 457 devices tested at 1800 MHz. However, in the largest studies, the prevalence of clinically relevant EMI was low. Most clinically relevant EMI occurred when mobile phones were used within 1 m of medical equipment. Although testing was not standardised between studies and equipment tested was not identical, it is of concern that at least 4% of devices tested in any study were susceptible to clinically relevant EMI. All studies recommend some type of restriction of mobile phone use in hospitals, with use greater than 1 m from equipment and restrictions in clinical areas being the most common.

Designing and Evaluating an Interactive Multimedia Web-Based Simulation for Developing Nurses’ Competencies in Acute Nursing Care: Randomized Controlled Trial

PubMed Central

Wong, Lai Fun; Chan, Sally Wai-Chi; Ho, Jasmine Tze Yin; Mordiffi, Siti Zubaidah; Ang, Sophia Bee Leng; Goh, Poh Sun; Ang, Emily Neo Kim

2015-01-01

Background Web-based learning is becoming an increasingly important instructional tool in nursing education. Multimedia advancements offer the potential for creating authentic nursing activities for developing nursing competency in clinical practice. Objective This study aims to describe the design, development, and evaluation of an interactive multimedia Web-based simulation for developing nurses’ competencies in acute nursing care. Methods Authentic nursing activities were developed in a Web-based simulation using a variety of instructional strategies including animation video, multimedia instructional material, virtual patients, and online quizzes. A randomized controlled study was conducted on 67 registered nurses who were recruited from the general ward units of an acute care tertiary hospital. Following a baseline evaluation of all participants’ clinical performance in a simulated clinical setting, the experimental group received 3 hours of Web-based simulation and completed a survey to evaluate their perceptions of the program. All participants were re-tested for their clinical performances using a validated tool. Results The clinical performance posttest scores of the experimental group improved significantly (P<.001) from the pretest scores after the Web-based simulation. In addition, compared to the control group, the experimental group had significantly higher clinical performance posttest scores (P<.001) after controlling the pretest scores. The participants from the experimental group were satisfied with their learning experience and gave positive ratings for the quality of the Web-based simulation. Themes emerging from the comments about the most valuable aspects of the Web-based simulation include relevance to practice, instructional strategies, and fostering problem solving. Conclusions Engaging in authentic nursing activities using interactive multimedia Web-based simulation can enhance nurses’ competencies in acute care. Web-based simulations provide a promising educational tool in institutions where large groups of nurses need to be trained in acute nursing care and accessibility to repetitive training is essential for achieving long-term retention of clinical competency. PMID:25583029

Designing and evaluating an interactive multimedia Web-based simulation for developing nurses' competencies in acute nursing care: randomized controlled trial.

PubMed

Liaw, Sok Ying; Wong, Lai Fun; Chan, Sally Wai-Chi; Ho, Jasmine Tze Yin; Mordiffi, Siti Zubaidah; Ang, Sophia Bee Leng; Goh, Poh Sun; Ang, Emily Neo Kim

2015-01-12

Web-based learning is becoming an increasingly important instructional tool in nursing education. Multimedia advancements offer the potential for creating authentic nursing activities for developing nursing competency in clinical practice. This study aims to describe the design, development, and evaluation of an interactive multimedia Web-based simulation for developing nurses' competencies in acute nursing care. Authentic nursing activities were developed in a Web-based simulation using a variety of instructional strategies including animation video, multimedia instructional material, virtual patients, and online quizzes. A randomized controlled study was conducted on 67 registered nurses who were recruited from the general ward units of an acute care tertiary hospital. Following a baseline evaluation of all participants' clinical performance in a simulated clinical setting, the experimental group received 3 hours of Web-based simulation and completed a survey to evaluate their perceptions of the program. All participants were re-tested for their clinical performances using a validated tool. The clinical performance posttest scores of the experimental group improved significantly (P<.001) from the pretest scores after the Web-based simulation. In addition, compared to the control group, the experimental group had significantly higher clinical performance posttest scores (P<.001) after controlling the pretest scores. The participants from the experimental group were satisfied with their learning experience and gave positive ratings for the quality of the Web-based simulation. Themes emerging from the comments about the most valuable aspects of the Web-based simulation include relevance to practice, instructional strategies, and fostering problem solving. Engaging in authentic nursing activities using interactive multimedia Web-based simulation can enhance nurses' competencies in acute care. Web-based simulations provide a promising educational tool in institutions where large groups of nurses need to be trained in acute nursing care and accessibility to repetitive training is essential for achieving long-term retention of clinical competency.

Herbal remedies and clinical biochemistry.

PubMed

Corns, Cathryn M

2003-09-01

The use of herbal products in the UK is increasing, and over-the-counter herbal supplements are perceived by the public as 'safe' and 'harmless'. Although the majority of them are safe, some herbal medicines carry risks. Heavy metal contamination, adulteration with Western pharmaceuticals and inclusion of prohibited animal and plant ingredients are regularly reported in ethnic medicines. Other herbs are hepato- or nephrotoxic and some interact with prescription medicines. Doctors should be made aware of the need to take a herbal as well as a drug history, and the clinical laboratory has a role in helping understanding of how herbal products may affect laboratory tests and in suggesting relevant lines of investigation in patients whose symptoms may be linked to the use of herbal products.

Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives.

PubMed

Ašić, Adna; Marjanović, Damir; Mirat, Jure; Primorac, Dragan

2018-05-16

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

Ticks and tick-borne diseases: a One Health perspective.

PubMed

Dantas-Torres, Filipe; Chomel, Bruno B; Otranto, Domenico

2012-10-01

Tick-borne diseases are common occurrences in both the medical and veterinary clinical settings. In addition to the constraints related to their diagnosis and clinical management, the control and prevention of these diseases is often difficult, because it requires the disruption of a complex transmission chain, involving vertebrate hosts and ticks, which interact in a constantly changing environment. We provide a contemporary review of representative tick-borne diseases of humans and discuss aspects linked to their medical relevance worldwide. Finally, we emphasize the importance of a One Health approach to tick-borne diseases, calling physicians and veterinarians to unify their efforts in the management of these diseases, several of which are zoonoses. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Tissue Relevance and Meshing Method for Computing Patient-Specific Anatomical Models in Endoscopic Sinus Surgery Simulation

NASA Astrophysics Data System (ADS)

Audette, M. A.; Hertel, I.; Burgert, O.; Strauss, G.

This paper presents on-going work on a method for determining which subvolumes of a patient-specific tissue map, extracted from CT data of the head, are relevant to simulating endoscopic sinus surgery of that individual, and for decomposing these relevant tissues into triangles and tetrahedra whose mesh size is well controlled. The overall goal is to limit the complexity of the real-time biomechanical interaction while ensuring the clinical relevance of the simulation. Relevant tissues are determined as the union of the pathology present in the patient, of critical tissues deemed to be near the intended surgical path or pathology, and of bone and soft tissue near the intended path, pathology or critical tissues. The processing of tissues, prior to meshing, is based on the Fast Marching method applied under various guises, in a conditional manner that is related to tissue classes. The meshing is based on an adaptation of a meshing method of ours, which combines the Marching Tetrahedra method and the discrete Simplex mesh surface model to produce a topologically faithful surface mesh with well controlled edge and face size as a first stage, and Almost-regular Tetrahedralization of the same prescribed mesh size as a last stage.

Potentially harmful drug-drug interactions in the elderly: a review.

PubMed

Hines, Lisa E; Murphy, John E

2011-12-01

Elderly patients are vulnerable to drug interactions because of age-related physiologic changes, an increased risk for disease associated with aging, and the consequent increase in medication use. The purpose of this narrative review was to describe findings from rigorously designed observational cohort and case-control studies that have assessed specific drug interactions in elderly patients. The PubMed and International Pharmaceutical Abstracts databases were searched for studies published in English over the past 10 years (December 2000-December 2010) using relevant Medical Subject Headings terms (aged; aged, 80 and over; and drug interactions) and search terms (drug interaction and elderly). Search strategies were saved and repeated through September 2011 to ensure that the most recent relevant published articles were identified. Additional articles were found using a search of review articles and reference lists of the identified studies. Studies were included if they were observational cohort or case-control studies that reported specific adverse drug interactions, included patients aged ≥65 years, and evaluated clinically meaningful end points. Studies were excluded if they used less rigorous observational designs, assessed pharmacokinetic/pharmacodynamic properties, evaluated drug-nutrient or drug-disease interactions or interactions of drug combinations used for therapeutic benefit (eg, dual antiplatelet therapy), or had inconclusive evidence. Seventeen studies met the inclusion criteria. Sixteen studies reported an elevated risk for hospitalization in older adults associated with adverse drug interactions. The drug interactions included: angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics, ACE inhibitors or angiotensin receptor blockers and sulfamethoxazole/trimethoprim, benzodiazepines or zolpidem and interacting medications, calcium channel blockers and macrolide antibiotics, digoxin and macrolide antibiotics, lithium and loop diuretics or ACE inhibitors, phenytoin and sulfamethoxazole/trimethoprim, sulfonylureas and antimicrobial agents, theophylline and ciprofloxacin, and warfarin and antimicrobial agents or nonsteroidal anti-inflammatory drugs. One study reported the risk for breast cancer-related death as a function of paroxetine exposure among women treated with tamoxifen. Several population-based studies have reported significant harm associated drug interactions in elderly patients. Increased awareness and interventions aimed at reducing exposure and minimizing the risks associated with potentially harmful drug combinations are needed. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Molecular understanding of Abeta peptide interaction with isoflurane, propofol, and thiopental: NMR spectroscopic study.

PubMed

Mandal, Pravat K; Williams, John P; Mandal, Ratna

2007-01-23

Abeta peptide is the major component of senile plaques (SP), which accumulate in the brain of a patient with Alzheimer's disease (AD). A recent report indicated that isoflurane enhanced Abeta oligomerization (micro-aggregation) and subsequent cytotoxicity of the Abeta peptide. A separate study showed that a clinically relevant concentration of isoflurane induces apoptosis and increases Abeta production in a human neuroglioma cell line. In vitro studies have indicated that halothane interacts specifically with Abeta peptide to induce oligomerization and that Abeta42 oligomerizes faster than Abeta40. The specific interactions of isoflurane, propofol, and thiopental with uniformly 15N labeled Abeta40 and Abeta42 peptide were investigated using multidimensional nuclear magnetic resonance (NMR) experiments. We found that isoflurane and propofol (at higher concentration) interact with Abeta40 peptides and induce Abeta oligomerization. Thiopental does not interact with specific residues (G29, A30, and I31) of Abeta40; hence, the peptide remains in the monomeric form. On the basis of our NMR study, thiopental does not oligomerize Abeta40 even at higher concentrations.

An ex vivo approach to botanical-drug interactions: A proof of concept study

PubMed Central

Wang, Xinwen; Zhu, Hao-Jie; Munoz, Juliana; Gurley, Bill J.; Markowitz, John S.

2015-01-01

Ethnopharmacological relevance Botanical medicines are frequently used in combination with therapeutic drugs, imposing a risk for harmful botanical-drug interactions (BDIs). Among the existing BDI evaluation methods, clinical studies are the most desirable, but due to their expense and protracted time-line for completion, conventional in vitro methodologies remain the most frequently used BDI assessment tools. However, many predictions generated from in vitro studies are inconsistent with clinical findings. Accordingly, the present study aimed to develop a novel ex vivo approach for BDI assessment and expand the safety evaluation methodoloy in applied ethnopharmacological research. Materials and Methods This approach differs from conventional in vitro methods in that rather than botanical extracts or individual phytochemicals being prepared in artificial buffers, human plasma/serum collected from a limited number of subjects administered botanical supplements was utilized to assess BDIs. To validate the methodology, human plasma/serum samples collected from healthy subjects administered either milk thistle or goldenseal extracts were utilized in incubation studies to determine their potential inhibitory effects on CYP2C9 and CYP3A4/5, respectively. Silybin A and B, two principal milk thistle phytochemicals, and hydrastine and berberine, the purported active constituents in goldenseal, were evaluated in both phosphate buffer and human plasma based in vitro incubation systems. Results Ex vivo study results were consistent with formal clinical study findings for the effect of milk thistle on the disposition of tolbutamide, a CYP2C9 substrate, and for goldenseal’s influence on the pharmacokinetics of midazolam, a widely accepted CYP3A4/5 substrate. Compared to conventional in vitro BDI methodologies of assessment, the introduction of human plasma into the in vitro study model changed the observed inhibitory effect of silybinA, silybin B and hydrastine and berberine on CYP2C9 and CYP3A4/5, respectively, results which more closely mirrored those generated in clinical study. Conclusions Data from conventional buffer-based in vitro studies were less predictive than the ex vivo assessments. Thus, this novel ex vivo approach may be more effective at predicting clinically relevant BDIs than conventional in vitro methods. PMID:25623616

Clinical relevance of findings in trials of CBT for depression.

PubMed

Lepping, P; Whittington, R; Sambhi, R S; Lane, S; Poole, R; Leucht, S; Cuijpers, P; McCabe, R; Waheed, W

2017-09-01

Cognitive behavioural therapy (CBT) is beneficial in depression. Symptom scores can be translated into Clinical Global Impression (CGI) scale scores to indicate clinical relevance. We aimed to assess the clinical relevance of findings of randomised controlled trials (RCTs) of CBT in depression. We identified RCTs of CBT that used the Hamilton Rating Scale for Depression (HAMD). HAMD scores were translated into Clinical Global Impression - Change scale (CGI-I) scores to measure clinical relevance. One hundred and seventy datasets from 82 studies were included. The mean percentage HAMD change for treatment arms was 53.66%, and 29.81% for control arms, a statistically significant difference. Combined active therapies showed the biggest improvement on CGI-I score, followed by CBT alone. All active treatments had better than expected HAMD percentage reduction and CGI-I scores. CBT has a clinically relevant effect in depression, with a notional CGI-I score of 2.2, indicating a significant clinical response. The non-specific or placebo effect of being in a psychotherapy trial was a 29% reduction of HAMD. Copyright © 2017. Published by Elsevier Masson SAS.

Immunological network signatures of cancer progression and survival

PubMed Central

2011-01-01

Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides. PMID:21453479

Drug development in neuropsychopharmacology.

PubMed

Fritze, Jürgen

2008-03-01

Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

A method for developing standardised interactive education for complex clinical guidelines

PubMed Central

2012-01-01

Background Although systematic use of the Perinatal Society of Australia and New Zealand internationally endorsed Clinical Practice Guideline for Perinatal Mortality (PSANZ-CPG) improves health outcomes, implementation is inadequate. Its complexity is a feature known to be associated with non-compliance. Interactive education is effective as a guideline implementation strategy, but lacks an agreed definition. SCORPIO is an educational framework containing interactive and didactic teaching, but has not previously been used to implement guidelines. Our aim was to transform the PSANZ-CPG into an education workshop to develop quality standardised interactive education acceptable to participants for learning skills in collaborative interprofessional care. Methods The workshop was developed using the construct of an educational framework (SCORPIO), the PSANZ-CPG, a transformation process and tutor training. After a pilot workshop with key target and stakeholder groups, modifications were made to this and subsequent workshops based on multisource written observations from interprofessional participants, tutors and an independent educator. This participatory action research process was used to monitor acceptability and educational standards. Standardised interactive education was defined as the attainment of content and teaching standards. Quantitative analysis of positive expressed as a percentage of total feedback was used to derive a total quality score. Results Eight workshops were held with 181 participants and 15 different tutors. Five versions resulted from the action research methodology. Thematic analysis of multisource observations identified eight recurring education themes or quality domains used for standardisation. The two content domains were curriculum and alignment with the guideline and the six teaching domains; overload, timing, didacticism, relevance, reproducibility and participant engagement. Engagement was the most challenging theme to resolve. Tutors identified all themes for revision whilst participants identified a number of teaching but no content themes. From version 1 to 5, a significant increasing trend in total quality score was obtained; participants: 55%, p=0.0001; educator: 42%, p=0.0004; tutor peers: 57%, p=0.0001. Conclusions Complex clinical guidelines can be developed into a workshop acceptable to interprofessional participants. Eight quality domains provide a framework to standardise interactive teaching for complex clinical guidelines. Tutor peer review is important for content validity. This methodology may be useful for other guideline implementation. PMID:23131137

A method for developing standardised interactive education for complex clinical guidelines.

PubMed

Vaughan, Janet I; Jeffery, Heather E; Raynes-Greenow, Camille; Gordon, Adrienne; Hirst, Jane; Hill, David A; Arbuckle, Susan

2012-11-06

Although systematic use of the Perinatal Society of Australia and New Zealand internationally endorsed Clinical Practice Guideline for Perinatal Mortality (PSANZ-CPG) improves health outcomes, implementation is inadequate. Its complexity is a feature known to be associated with non-compliance. Interactive education is effective as a guideline implementation strategy, but lacks an agreed definition. SCORPIO is an educational framework containing interactive and didactic teaching, but has not previously been used to implement guidelines. Our aim was to transform the PSANZ-CPG into an education workshop to develop quality standardised interactive education acceptable to participants for learning skills in collaborative interprofessional care. The workshop was developed using the construct of an educational framework (SCORPIO), the PSANZ-CPG, a transformation process and tutor training. After a pilot workshop with key target and stakeholder groups, modifications were made to this and subsequent workshops based on multisource written observations from interprofessional participants, tutors and an independent educator. This participatory action research process was used to monitor acceptability and educational standards. Standardised interactive education was defined as the attainment of content and teaching standards. Quantitative analysis of positive expressed as a percentage of total feedback was used to derive a total quality score. Eight workshops were held with 181 participants and 15 different tutors. Five versions resulted from the action research methodology. Thematic analysis of multisource observations identified eight recurring education themes or quality domains used for standardisation. The two content domains were curriculum and alignment with the guideline and the six teaching domains; overload, timing, didacticism, relevance, reproducibility and participant engagement. Engagement was the most challenging theme to resolve. Tutors identified all themes for revision whilst participants identified a number of teaching but no content themes. From version 1 to 5, a significant increasing trend in total quality score was obtained; participants: 55%, p=0.0001; educator: 42%, p=0.0004; tutor peers: 57%, p=0.0001. Complex clinical guidelines can be developed into a workshop acceptable to interprofessional participants. Eight quality domains provide a framework to standardise interactive teaching for complex clinical guidelines. Tutor peer review is important for content validity. This methodology may be useful for other guideline implementation.

Theory of mind, social development, and psychosis.

PubMed

Casacchia, Massimo; Mazza, Monica; Roncone, Rita

2004-06-01

The difficulty in interpreting other people's mental states found in children with autism and in people affected by schizophrenia may be explained in terms of a unique mental process called Theory of Mind. The paper discusses the main operational issues of such a peculiar aspect of social cognition, the Theory of Mind, and its implication in schizophrenia, including a review of its related neural structures. Theory of Mind abilities may be a relevant aspect of social interaction involving people affected by schizophrenia, and they need to be further investigated in clinical research.

Academic-industrial partnerships in drug discovery in the age of genomics.

PubMed

Harris, Tim; Papadopoulos, Stelios; Goldstein, David B

2015-06-01

Many US FDA-approved drugs have been developed through productive interactions between the biotechnology industry and academia. Technological breakthroughs in genomics, in particular large-scale sequencing of human genomes, is creating new opportunities to understand the biology of disease and to identify high-value targets relevant to a broad range of disorders. However, the scale of the work required to appropriately analyze large genomic and clinical data sets is challenging industry to develop a broader view of what areas of work constitute precompetitive research. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bioreactor Engineering of Stem Cell Environments

PubMed Central

Tandon, Nina; Marolt, Darja; Cimetta, Elisa; Vunjak-Novakovic, Gordana

2013-01-01

Stem cells hold promise to revolutionize modern medicine by development of new therapies, disease models and drug screening systems. Standard cell culture systems have limited biological relevance because they do not recapitulate the complex 3-dimensional interactions and biophysical cues that characterize the in vivo environment. In this review, we discuss the current advances in engineering stem cell environments using novel biomaterials and bioreactor technologies. We also reflect on the challenges the field is currently facing with regard to translation of stem cell based therapies into the clinic. PMID:23531529

The Acquisition of Drugs and Biologics for Chemical and Biological Warfare Defense. Department of Defense Interactions with the Food and Drug Administration

DTIC Science & Technology

2003-01-01

implementing regulations in the Code of Federal Regulations Title 21 ( 21 CFR). We searched the literature for relevant documents, especially for the type...public health activity at the end of the 19th century . The Bio- logics Control Act of 1902 authorizes their regulation under the PHSA.4 From the end of...regulations are codified 21 CFR: Preclinical studies must be conducted according to Good Labo- ratory Practices (GLPs); clinical studies in accordance with

Dynamic Effects of Self-Relevance and Task on the Neural Processing of Emotional Words in Context

PubMed Central

Fields, Eric C.; Kuperberg, Gina R.

2016-01-01

We used event-related potentials (ERPs) to examine the interactions between task, emotion, and contextual self-relevance on processing words in social vignettes. Participants read scenarios that were in either third person (other-relevant) or second person (self-relevant) and we recorded ERPs to a neutral, pleasant, or unpleasant critical word. In a previously reported study (Fields and Kuperberg, 2012) with these stimuli, participants were tasked with producing a third sentence continuing the scenario. We observed a larger LPC to emotional words than neutral words in both the self-relevant and other-relevant scenarios, but this effect was smaller in the self-relevant scenarios because the LPC was larger on the neutral words (i.e., a larger LPC to self-relevant than other-relevant neutral words). In the present work, participants simply answered comprehension questions that did not refer to the emotional aspects of the scenario. Here we observed quite a different pattern of interaction between self-relevance and emotion: the LPC was larger to emotional vs. neutral words in the self-relevant scenarios only, and there was no effect of self-relevance on neutral words. Taken together, these findings suggest that the LPC reflects a dynamic interaction between specific task demands, the emotional properties of a stimulus, and contextual self-relevance. We conclude by discussing implications and future directions for a functional theory of the emotional LPC. PMID:26793138

Lack of interaction between thioctic acid, glibenclamide and acarbose

PubMed Central

Gleiter, C H; Schreeb, K H; Freudenthaler, S; Thomas, M; Elze, M; Fieger-Büschges, H; Potthast, H; Schneider, E; Schug, B S; Blume, H H; Hermann, R

1999-01-01

Aims Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin-dependent diabetes (NIDDM). This study systematically investigated drug–drug interactions between TA and glibenclamide and TA and acarbose. Methods Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A–C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(−)-TA as well as glibenclamide concentrations were measured with specific analytical methods. Results There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide. Conclusions Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug–drug interactions. PMID:10594485

Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update.

PubMed

Mohn, Emily S; Kern, Hua J; Saltzman, Edward; Mitmesser, Susan H; McKay, Diane L

2018-03-20

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug-nutrient interactions is quite limited. A comprehensive, updated review of the potential drug-nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.

Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update

PubMed Central

Mohn, Emily S.; Kern, Hua J.; Saltzman, Edward; Mitmesser, Susan H.; McKay, Diane L.

2018-01-01

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is quite limited. A comprehensive, updated review of the potential drug–nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care. PMID:29558445

New Dimensions in Patient–Physician Interaction: Values, Autonomy, and Medical Information in the Patient-Centered Clinical Encounter

PubMed Central

Agarwal, Aakash Kumar; Murinson, Beth Brianna

2012-01-01

Patient–physician interactions are increasingly influenced by the extraordinary diversification of populations and rapid expansion of medical knowledge that characterize our modern era. By contrast, the patient–physician interaction models currently used to teach medical trainees have little capacity to address these twin challenges. We developed a new model of patient–physician interaction to explicitly address these problems. Historically, models of patient–physician interaction viewed patient autonomy and the manifestation of clearly defined health care-related values as tightly linked, and it was assumed that patients’ medical knowledge was low. Unfortunately, this does not adequately represent patients such as 1) the highly educated non-medical specialist who possesses little familiarity with health-related values but is highly autonomous, and 2) the patient from a non-Western background who may have well-established health care-related values but a low sense of personal independence. In addition, it is evident to us that the assumption that all patients possess little medical knowledge can create alienation between patient and physician, e.g. the well-informed patient with a rare disease. We propose a paradigm that models autonomy, health care-related values formation, and medical knowledge as varying from patient to patient. Four examples of patient types are described within the context of the model based on clinical experience. We believe that adopting this model will have implications for optimizing patient–physician interactions and teaching about patient-centered care. Further research is needed to identify relevant patient types within this framework and to assess the impact on health care outcomes. PMID:23908841

What's hot, what's new in basic science: report from the American Transplant Congress 2015.

PubMed

Heeger, P S

2015-11-01

Research reports presented at the American Transplant Congress 2015 provided an array of basic science findings of relevance to the transplant community. Among key themes is the concept that ischemia-reperfusion injury and early posttransplantation inflammation is linked to adaptive alloimmunity and transplant injury. Molecular and cellular mechanisms contributing to these interactions were highlighted. The relevance of understanding how blocking costimulation, including CD40/CD154 interactions, affects various aspects of the alloimmune response was enhanced by the description of preclinical studies demonstrating efficacy of a unique, blocking anti-CD40 monoclonal antibody that could potentially be used in humans. The identification of mechanisms underlying interactions among T cell subsets and B cells, including follicular helper T cells, regulatory T cells, effector B cells, and regulatory B cells, provides multiple previously unrecognized targets for future therapeutic interventions. Additional reports of interest include novel insights into effects of the gut microbiome on graft survival and the ability to differentiate insulin-secreting, islet-like cells from induced pluripotent stem cells. Overall, the reported basic science findings from American Transplant Congress 2015 add to the fundamental understanding of innate and adaptive alloimmunity and provide novel and testable hypotheses that have the potential to be translated into improved clinical care of transplant patients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Predictive performance of three practical approaches for grapefruit juice-induced 2-fold or greater increases in AUC of concomitantly administered drugs.

PubMed

Takahashi, M; Onozawa, S; Ogawa, R; Uesawa, Y; Echizen, H

2015-02-01

Clinical pharmacists have a challenging task when answering patients' question about whether they can take specific drugs with grapefruit juice (GFJ) without risk of drug interaction. To identify the most practicable method for predicting clinically relevant changes in plasma concentrations of orally administered drugs caused by the ingestion of GFJ, we compared the predictive performance of three methods using data obtained from the literature. We undertook a systematic search of drug interactions associated with GFJ using MEDLINE and the Metabolism & Transport Drug Interaction Database (DIDB version 4.0). We considered an elevation of the area under the plasma concentration-time curve (AUC) of 2 or greater relative to the control value [AUC ratio (AUCR) ≥ 2.0] as a clinically significant interaction. The data from 74 drugs (194 data sets) were analysed. When the reported information of CYP3A involvement in the metabolism of a drug of interest was adopted as a predictive criterion for GFJ-drug interaction, the performance assessed by positive predictive value (PPV) was low (0.26), but that assessed by negative predictive value (NPV) and sensitivity was high (1.00 for both). When the reported oral bioavailability of ≤ 0.1 was used as a criterion, the PPV improved to 0.50 with an acceptable NPV of 0.81, but sensitivity was reduced to 0.21. When the reported AUCR was ≥ 10 after co-administration of a typical CYP3A inhibitor, the corresponding values were 0.64, 0.79 and 0.19, respectively. We consider that an oral bioavailability of ≤ 0.1 or an AUCR of ≥ 10 caused by a CYP3A inhibitor of a drug of interest may be a practical prediction criterion for avoiding significant interactions with GFJ. Information about the involvement of CYP3A in their metabolism should also be taken into account for drugs with narrow therapeutic ranges. © 2014 John Wiley & Sons Ltd.

The gut microbiota and the liver: implications for clinical practice.

PubMed

Quigley, Eamonn M; Monsour, Howard P

2013-11-01

While a central role for the microbiota in the precipitation of infectious and non-infectious complications of liver disease has been long established, evidence for a more fundamental role in the etiology of several liver diseases continues to accumulate. However, though progress is rapidly occurring in this area, the definitive delineation of the precise relevance of changes in the microbiota to various forms and stages of liver disease is still far from complete. While high quality clinical evidence supports the use of antibiotic therapy, in the management of hepatic encephalopathy, spontaneous bacterial peritonitis and other infectious complications, how these interventions impact on the microbiota and microbiota-host interactions has not been clearly defined. Although probiotics and even, perhaps, fecal transplantation hold promise in the management of liver disease, and the potential impact of probiotics is supported by a considerable amount of laboratory data, high-quality clinical evidence is scanty.

Investigating a self-scoring interview simulation for learning and assessment in the medical consultation.

PubMed

Bruen, Catherine; Kreiter, Clarence; Wade, Vincent; Pawlikowska, Teresa

2017-01-01

Experience with simulated patients supports undergraduate learning of medical consultation skills. Adaptive simulations are being introduced into this environment. The authors investigate whether it can underpin valid and reliable assessment by conducting a generalizability analysis using IT data analytics from the interaction of medical students (in psychiatry) with adaptive simulations to explore the feasibility of adaptive simulations for supporting automated learning and assessment. The generalizability (G) study was focused on two clinically relevant variables: clinical decision points and communication skills. While the G study on the communication skills score yielded low levels of true score variance, the results produced by the decision points, indicating clinical decision-making and confirming user knowledge of the process of the Calgary-Cambridge model of consultation, produced reliability levels similar to what might be expected with rater-based scoring. The findings indicate that adaptive simulations have potential as a teaching and assessment tool for medical consultations.

Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z

PubMed Central

Sciacchitano, Salvatore; Lavra, Luca; Morgante, Alessandra; Ulivieri, Alessandra; Magi, Fiorenza; De Francesco, Gian Paolo; Bellotti, Carlo; Salehi, Leila B.; Ricci, Alberto

2018-01-01

Galectin-3 (Gal-3) regulates basic cellular functions such as cell–cell and cell–matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed. PMID:29373564

Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative.

PubMed

Garcia, Sofia F; Cella, David; Clauser, Steven B; Flynn, Kathryn E; Lad, Thomas; Lai, Jin-Shei; Reeve, Bryce B; Smith, Ashley Wilder; Stone, Arthur A; Weinfurt, Kevin

2007-11-10

Patient-reported outcomes (PROs), such as symptom scales or more broad-based health-related quality-of-life measures, play an important role in oncology clinical trials. They frequently are used to help evaluate cancer treatments, as well as for supportive and palliative oncology care. To be most beneficial, these PROs must be relevant to patients and clinicians, valid, and easily understood and interpreted. The Patient-Reported Outcomes Measurement Information System (PROMIS) Network, part of the National Institutes of Health Roadmap Initiative, aims to improve appreciably how PROs are selected and assessed in clinical research, including clinical trials. PROMIS is establishing a publicly available resource of standardized, accurate, and efficient PRO measures of major self-reported health domains (eg, pain, fatigue, emotional distress, physical function, social function) that are relevant across chronic illnesses including cancer. PROMIS is also developing measures of self-reported health domains specifically targeted to cancer, such as sleep/wake function, sexual function, cognitive function, and the psychosocial impacts of the illness experience (ie, stress response and coping; shifts in self-concept, social interactions, and spirituality). We outline the qualitative and quantitative methods by which PROMIS measures are being developed and adapted for use in clinical oncology research. At the core of this activity is the formation and application of item banks using item response theory modeling. We also present our work in the fatigue domain, including a short-form measure, as a sample of PROMIS methodology and work to date. Plans for future validation and application of PROMIS measures are discussed.

Clinicomanometric factors associated with clinically relevant esophagogastric junction outflow obstruction from the Sandhill high-resolution manometry system.

PubMed

Song, B G; Min, Y W; Lee, H; Min, B-H; Lee, J H; Rhee, P-L; Kim, J J

2018-03-01

Integrated relaxation pressure (IRP) is a key metric for diagnosing esophagogastric junction outflow obstruction (EGJOO). However, its normal value might be different according to the manufacturer of high-resolution manometry (HRM). This study aimed to investigate optimal value of IRP for diagnosing EGJOO in Sandhill HRM and to find clinicomanometric variables to segregate clinically relevant EGJOO. We analyzed 262 consecutive subjects who underwent HRM between June 2011 and December 2016 showing elevated median IRP (> 15 mm Hg) but did not satisfy criteria for achalasia. Clinically relevant subjects were defined as follows: (i) subsequent HRM met achalasia criteria during follow-up (early achalasia); (ii) Eckardt score was decreased at least two points without exceeding a score of 3 after pneumatic dilatation (variant achalasia); and (iii) significant passage disturbance on esophagogram without structural abnormality (possible achalasia). Seven subjects were clinically relevant, including two subjects with early achalasia, four subjects with variant achalasia, and one subject with possible achalasia. All clinically relevant subjects had IRP 20 mm Hg or above. Among subjects (n = 122) with IRP 20 mm Hg or more, clinically relevant group (n = 7) had significantly higher rate of dysphagia (100% vs 24.3%, P < .001) and compartmentalized pressurization (85.7% vs 21.7%, P = .001) compared to clinically non-relevant group (n = 115). Our results suggest that IRP of 20 mm Hg or higher could segregate clinically relevant subjects showing EGJOO in Sandhill HRM. Additionally, if subjects have both dysphagia and compartmentalized pressurization, careful follow-up is essential. © 2017 John Wiley & Sons Ltd.

An activity theory perspective of how scenario-based simulations support learning: a descriptive analysis.

PubMed

Battista, Alexis

2017-01-01

The dominant frameworks for describing how simulations support learning emphasize increasing access to structured practice and the provision of feedback which are commonly associated with skills-based simulations. By contrast, studies examining student participants' experiences during scenario-based simulations suggest that learning may also occur through participation. However, studies directly examining student participation during scenario-based simulations are limited. This study examined the types of activities student participants engaged in during scenario-based simulations and then analyzed their patterns of activity to consider how participation may support learning. Drawing from Engeström's first-, second-, and third-generation activity systems analysis, an in-depth descriptive analysis was conducted. The study drew from multiple qualitative methods, namely narrative, video, and activity systems analysis, to examine student participants' activities and interaction patterns across four video-recorded simulations depicting common motivations for using scenario-based simulations (e.g., communication, critical patient management). The activity systems analysis revealed that student participants' activities encompassed three clinically relevant categories, including (a) use of physical clinical tools and artifacts, (b) social interactions, and (c) performance of structured interventions. Role assignment influenced participants' activities and the complexity of their engagement. Importantly, participants made sense of the clinical situation presented in the scenario by reflexively linking these three activities together. Specifically, student participants performed structured interventions, relying upon the use of physical tools, clinical artifacts, and social interactions together with interactions between students, standardized patients, and other simulated participants to achieve their goals. When multiple student participants were present, such as in a team-based scenario, they distributed the workload to achieve their goals. The findings suggest that student participants learned as they engaged in these scenario-based simulations when they worked to make sense of the patient's clinical presentation. The findings may provide insight into how student participants' meaning-making efforts are mediated by the cultural artifacts (e.g., physical clinical tools) they access, the social interactions they engage in, the structured interventions they perform, and the roles they are assigned. The findings also highlight the complex and emergent properties of scenario-based simulations as well as how activities are nested. Implications for learning, instructional design, and assessment are discussed.

Justice in international clinical research.

PubMed

Pratt, Bridget; Loff, Bebe

2011-08-01

Debates about justice in international clinical research problematically conflate two quite different forms of obligation. International research ethics guidelines were intended to describe how to conduct biomedical research in a just manner at the micro or clinical level (within the researcher-participant interaction) but have come to include requirements that are clearly intended to promote justice at the global level. Ethicists have also made a variety of claims regarding what international research should contribute to global justice. This paper argues that the conflation of debates about justice at the micro and macro-levels has not only resulted in the placement of obligations upon the wrong actors but has also served to exclude relevant actors from the ethical picture. Suggestions for who should properly bear macro-level obligations of justice in international clinical research are offered. The paper further contends that, unlike researchers who violate informed consent requirements, no similar type of accountability exists for obligations of global justice, even for those obligation-bearers (incorrectly) identified by current ethics guidelines. © 2010 Blackwell Publishing Ltd.

"Just-in-time" clinical information.

PubMed

Chueh, H; Barnett, G O

1997-06-01

The just-in-time (JIT) model originated in the manufacturing industry as a way to manage parts inventories process so that specific components could be made available at the appropriate times (that is, "just in time"). This JIT model can be applied to the management of clinical information inventories, so that clinicians can have more immediate access to the most current and relevant information at the time they most need it--when making clinical care decisions. The authors discuss traditional modes of managing clinical information, and then describe how a new, JIT model may be developed and implemented. They describe three modes of clinician-information interactions that a JIT model might employ, the scope of information that may be made available in a JIT model (global information or local, case-specific information), and the challenges posed by the implementation of such an information-access model. Finally, they discuss how JIT information access may change how physicians practice medicine, various ways JIT information may be delivered, and concerns about the trustworthiness of electronically published and accessed information resources.

A Blended Learning Course Design in Clinical Pharmacology for Post-graduate Dental Students

PubMed Central

Rosenbaum, Paul-Erik Lillholm; Mikalsen, Øyvind; Lygre, Henning; Solheim, Einar; Schjøtt, Jan

2012-01-01

Postgraduate courses in clinical pharmacology are important for dentists to be updated on drug therapy and information related to their clinical practice, as well as knowledge of relevant adverse effects and interactions. A traditional approach with classroom delivery as the only method to teaching and learning has shortcomings regarding flexibility, individual learning preferences, and problem based learning (PBL) activities compared to online environments. This study examines a five week postgraduate course in clinical pharmacology with 15 hours of lectures and online learning activities, i.e. blended course design. Six postgraduate dental students participated and at the end of the course they were interviewed. Our findings emphasize that a blended learning course design can be successfully used in postgraduate dental education. Key matters for discussion were time flexibility and location convenience, change in teacher’s role, rein-forced learning strategies towards professional needs, scarcity in online communication, and proposed future utilization of e-learning components. PMID:23248716

Clinical and practical considerations in the pharmacologic management of narcolepsy.

PubMed

Thorpy, Michael J; Dauvilliers, Yves

2015-01-01

Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (ie, alcohol, nicotine, caffeine, and cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (eg, Epworth Sleepiness Scale and Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance the effective management of patients with narcolepsy. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system.

PubMed

Budak, Erdal; Fernández Sánchez, Manuel; Bellver, José; Cerveró, Ana; Simón, Carlos; Pellicer, Antonio

2006-06-01

To summarize the effects of novel hormones (leptin, ghrelin, adiponectin, resistin, and PYY3-36) secreted from adipose tissue and the gastrointestinal tract that have been discovered to exert different effects on several reproductive functions, such as the hypothalamic-pituitary-gonadal axis, embryo development, implantation physiology, and clinically relevant conditions. A MEDLINE computer search was performed to identify relevant articles. Leptin and ghrelin exert important roles on body weight regulation, eating behavior, and reproduction, acting on the central nervous system and target reproductive organs. As a marker of adequate nutritional stores, these hormones may act on the central nervous system to initiate the complex process of puberty and maintain normal reproductive function. In addition, leptin and ghrelin and their receptors are involved in reproductive events such as gonadal function, embryo development, and embryo-endometrial interaction. Leptin and ghrelin and other adipose tissue-secreted hormones have significant effects on reproduction. Acting through the brain, these hormones may serve as links between adipose tissue and the reproductive system to supply and regulate energy needs for normal reproduction and pregnancy. Future studies are needed to further clarify the role of these hormones in reproductive events and other related gynecological conditions.

Brain-Computer Interfaces: A Neuroscience Paradigm of Social Interaction? A Matter of Perspective

PubMed Central

Mattout, Jérémie

2012-01-01

A number of recent studies have put human subjects in true social interactions, with the aim of better identifying the psychophysiological processes underlying social cognition. Interestingly, this emerging Neuroscience of Social Interactions (NSI) field brings up challenges which resemble important ones in the field of Brain-Computer Interfaces (BCI). Importantly, these challenges go beyond common objectives such as the eventual use of BCI and NSI protocols in the clinical domain or common interests pertaining to the use of online neurophysiological techniques and algorithms. Common fundamental challenges are now apparent and one can argue that a crucial one is to develop computational models of brain processes relevant to human interactions with an adaptive agent, whether human or artificial. Coupled with neuroimaging data, such models have proved promising in revealing the neural basis and mental processes behind social interactions. Similar models could help BCI to move from well-performing but offline static machines to reliable online adaptive agents. This emphasizes a social perspective to BCI, which is not limited to a computational challenge but extends to all questions that arise when studying the brain in interaction with its environment. PMID:22675291

Interpretation of Blood Microbiology Results - Function of the Clinical Microbiologist.

PubMed

Kristóf, Katalin; Pongrácz, Júlia

2016-04-01

The proper use and interpretation of blood microbiology results may be one of the most challenging and one of the most important functions of clinical microbiology laboratories. Effective implementation of this function requires careful consideration of specimen collection and processing, pathogen detection techniques, and prompt and precise reporting of identification and susceptibility results. The responsibility of the treating physician is proper formulation of the analytical request and to provide the laboratory with complete and precise patient information, which are inevitable prerequisites of a proper testing and interpretation. The clinical microbiologist can offer advice concerning the differential diagnosis, sampling techniques and detection methods to facilitate diagnosis. Rapid detection methods are essential, since the sooner a pathogen is detected, the better chance the patient has of getting cured. Besides the gold-standard blood culture technique, microbiologic methods that decrease the time in obtaining a relevant result are more and more utilized today. In the case of certain pathogens, the pathogen can be identified directly from the blood culture bottle after propagation with serological or automated/semi-automated systems or molecular methods or with MALDI-TOF MS (matrix-assisted laser desorption-ionization time of flight mass spectrometry). Molecular biology methods are also suitable for the rapid detection and identification of pathogens from aseptically collected blood samples. Another important duty of the microbiology laboratory is to notify the treating physician immediately about all relevant information if a positive sample is detected. The clinical microbiologist may provide important guidance regarding the clinical significance of blood isolates, since one-third to one-half of blood culture isolates are contaminants or isolates of unknown clinical significance. To fully exploit the benefits of blood culture and other (non- culture based) diagnoses, the microbiologist and the clinician should interact directly.

Protein-engineered block-copolymers as stem cell delivery vehicles

NASA Astrophysics Data System (ADS)

Heilshorn, Sarah

2015-03-01

Stem cell transplantation is a promising therapy for a myriad of debilitating diseases and injuries; however, current delivery protocols are inadequate. Transplantation by direct injection, which is clinically preferred for its minimal invasiveness, commonly results in less than 5% cell viability, greatly inhibiting clinical outcomes. We demonstrate that mechanical membrane disruption results in significant acute loss of viability at clinically relevant injection rates. As a strategy to protect cells from these damaging forces, we show that cell encapsulation within hydrogels of specific mechanical properties will significantly improve viability. Building on these fundamental studies, we have designed a reproducible, bio-resorbable, customizable hydrogel using protein-engineering technology. In our Mixing-Induced Two-Component Hydrogel (MITCH), network assembly is driven by specific and stoichiometric peptide-peptide binding interactions. By integrating protein science methodologies with simple polymer physics models, we manipulate the polypeptide chain interactions and demonstrate the direct ability to tune the network crosslinking density, sol-gel phase behavior, and gel mechanics. This is in contrast to many other physical hydrogels, where predictable tuning of bulk mechanics from the molecular level remains elusive due to the reliance on non-specific and non-stoichiometric chain interactions for network formation. Furthermore, the hydrogel network can be easily modified to deliver a variety of bioactive payloads including growth factors, peptide drugs, and hydroxyapatite nanoparticles. Through a series of in vitro and in vivo studies, we demonstrate that these materials may significantly improve transplanted stem cell retention and function.

The COPD Knowledge Base: enabling data analysis and computational simulation in translational COPD research.

PubMed

Cano, Isaac; Tényi, Ákos; Schueller, Christine; Wolff, Martin; Huertas Migueláñez, M Mercedes; Gomez-Cabrero, David; Antczak, Philipp; Roca, Josep; Cascante, Marta; Falciani, Francesco; Maier, Dieter

2014-11-28

Previously we generated a chronic obstructive pulmonary disease (COPD) specific knowledge base (http://www.copdknowledgebase.eu) from clinical and experimental data, text-mining results and public databases. This knowledge base allowed the retrieval of specific molecular networks together with integrated clinical and experimental data. The COPDKB has now been extended to integrate over 40 public data sources on functional interaction (e.g. signal transduction, transcriptional regulation, protein-protein interaction, gene-disease association). In addition we integrated COPD-specific expression and co-morbidity networks connecting over 6 000 genes/proteins with physiological parameters and disease states. Three mathematical models describing different aspects of systemic effects of COPD were connected to clinical and experimental data. We have completely redesigned the technical architecture of the user interface and now provide html and web browser-based access and form-based searches. A network search enables the use of interconnecting information and the generation of disease-specific sub-networks from general knowledge. Integration with the Synergy-COPD Simulation Environment enables multi-scale integrated simulation of individual computational models while integration with a Clinical Decision Support System allows delivery into clinical practice. The COPD Knowledge Base is the only publicly available knowledge resource dedicated to COPD and combining genetic information with molecular, physiological and clinical data as well as mathematical modelling. Its integrated analysis functions provide overviews about clinical trends and connections while its semantically mapped content enables complex analysis approaches. We plan to further extend the COPDKB by offering it as a repository to publish and semantically integrate data from relevant clinical trials. The COPDKB is freely available after registration at http://www.copdknowledgebase.eu.

Long duration mild temperature hyperthermia and brachytherapy.

PubMed

Armour, E P; Raaphorst, G P

2004-03-01

Combining long duration mild temperature hyperthermia (LDMH) and low dose-rate (LDR) brachytherapy to enhance therapeutic killing of cancer cells was proposed many years ago. The cellular and tumour research that supports this hypothesis is presented in this review. Research describing LDMH interaction with pulsed brachytherapy and high dose-rate brachytherapy using clinically relevant parameters are compared with LDMH/LDR brachytherapy. The mechanism by which LDMH sensitizes LDR has been established as the inhibition of sublethal damage repair. The molecular mechanisms have been shown to involve DNA repair enzymes, but the exact nature of these processes is still under investigation. The relative differences between LDMH interactions with human and rodent cells are presented to help in the understanding of possible roles of LDMH in clinical application. The role of LDMH in modifying tumour blood flow and its possible role in LDR sensitization of tumours is also presented. The positive aspects of LDMH-brachytherapy for clinical application are sixfold; (1) the thermal goals (temperature, time and volume) are achievable with currently available technology, (2) the hyperthermia by itself has no detectable toxic effects, (3) thermotolerance appears to play a minor if any role in radiation sensitization, (4) TER of around 2 can be expected, (5) hypoxic fraction may be decreased due to blood flow modification and (6) simultaneous chemotherapy may also be sensitized. Combined LDMH and brachytherapy is a cancer therapy that has established biological rationale and sufficient technical and clinical advancements to be appropriately applied. This modality is ripe for clinical testing.

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

PubMed Central

Iffland, Kerstin; Grotenhermen, Franjo

2017-01-01

Abstract Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs. Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients' compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam's side effects. Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking. PMID:28861514

Use of Information and Communication Technologies in Clinical Practice Related to the Treatment of Pain. Influence on the Professional Activity and the Doctor-Patient Relationship.

PubMed

Fernandez, Jorge Muriel; Cenador, Maria Begoña García; Manuel López Millan, J; Méndez, Juan Antonio Juanes; Ledesma, María José Sánchez

2017-05-01

The increasing relevance of Information and Communication Technologies (ICTs) in medical care is indisputable. This evidence makes it necessary to start studies that analyse the scope these new forms of access to information and understanding of medicine have on the professional activity of the physician, on the attitude and on the knowledge of patients or, on the doctor-patient relationship. The purpose of this study is to explore some of these aspects in a group of physicians whose clinical activity is related to one of the greatest social impact health problems which is the treatment of chronic pain. Starting with the completion of a questionnaire, in the study group it is observed that the interaction between social structure, increase of information flows and ICTs generate transformations in social practices and behaviour of the actors of the health system. Internet is confirmed as an information space on the subject, but is shown as an underutilized space of interaction between the doctor and his patient.

Decoupling Polymer Properties to Elucidate Mechanisms Governing Cell Behavior

PubMed Central

Wang, Xintong; Boire, Timothy C.; Bronikowski, Christine; Zachman, Angela L.; Crowder, Spencer W.

2012-01-01

Determining how a biomaterial interacts with cells (“structure-function relationship”) reflects its eventual clinical applicability. Therefore, a fundamental understanding of how individual material properties modulate cell-biomaterial interactions is pivotal to improving the efficacy and safety of clinically translatable biomaterial systems. However, due to the coupled nature of material properties, their individual effects on cellular responses are difficult to understand. Structure-function relationships can be more clearly understood by the effective decoupling of each individual parameter. In this article, we discuss three basic decoupling strategies: (1) surface modification, (2) cross-linking, and (3) combinatorial approaches (i.e., copolymerization and polymer blending). Relevant examples of coupled material properties are briefly reviewed in each section to highlight the need for improved decoupling methods. This follows with examples of more effective decoupling techniques, mainly from the perspective of three primary classes of synthetic materials: polyesters, polyethylene glycol, and polyacrylamide. Recent strides in decoupling methodologies, especially surface-patterning and combinatorial techniques, offer much promise in further understanding the structure-function relationships that largely govern the success of future advancements in biomaterials, tissue engineering, and drug delivery. PMID:22536977

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.

PubMed

Jacobsen, Jacob P R; Plenge, Per; Sachs, Benjamin D; Pehrson, Alan L; Cajina, Manuel; Du, Yunzhi; Roberts, Wendy; Rudder, Meghan L; Dalvi, Prachiti; Robinson, Taylor J; O'Neill, Sharon P; Khoo, King S; Morillo, Connie Sanchez; Zhang, Xiaodong; Caron, Marc G

2014-12-01

Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of. Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration. We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.

Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects.

PubMed

Graefe-Mody, Ulrike; Rose, Peter; Ring, Arne; Zander, Kerstin; Iovino, Mario; Woerle, Hans-Juergen

2011-01-01

The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day × 6 days) and single doses of glyburide (1.75 mg/day × 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 18-55 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC(τ,ss) and C(max,ss) were 101.7% [97.7-105.8%] and 100.8% [89.0-114.3%], respectively. For glyburide, there was a slight reduction in exposure of ∼14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC(0-∞) and C(max) were 85.7% [79.8-92.1%] and 86.2% [79.6-93.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable dose-response relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments.

Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery

PubMed Central

Bønnelykke, Klaus; Ober, Carole

2016-01-01

Asthma is a heterogeneous clinical syndrome that includes subtypes of disease with different underlying causes and disease mechanisms. Asthma is caused by a complex interaction between genes and environmental exposures; early-life exposures in particular play an important role. Asthma is also heritable, and a number of susceptibility variants have been discovered in genome-wide association studies, although the known risk alleles explain only a small proportion of the heritability. In this review, we present evidence supporting the hypothesis that focusing on more specific asthma phenotypes, such as childhood asthma with severe exacerbations, and on relevant exposures that are involved in gene-environment interactions (GEIs), such as rhinovirus infections, will improve detection of asthma genes and our understanding of the underlying mechanisms. We will discuss the challenges of considering GEIs and the advantages of studying responses to asthma-associated exposures in clinical birth cohorts, as well as in cell models of GEIs, to dissect the context-specific nature of genotypic risks, to prioritize variants in genome-wide association studies, and to identify pathways involved in pathogenesis in subgroups of patients. We propose that such approaches, in spite of their many challenges, present great opportunities for better understanding of asthma pathogenesis and heterogeneity and, ultimately, for improving prevention and treatment of disease. PMID:26947980

Interactive effects of N-acetylcysteine and antidepressants.

PubMed

Costa-Campos, Luciane; Herrmann, Ana P; Pilz, Luísa K; Michels, Marcus; Noetzold, Guilherme; Elisabetsky, Elaine

2013-07-01

N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression. Copyright © 2013 Elsevier Inc. All rights reserved.

[Acne vulgaris: morphologic, endocrinologic and psychosomatic aspects].

PubMed

Welp, K; Gieler, U

1990-12-01

25 male patients suffering from acne vulgaris were examined by means of endocrinological, morphological, and 5 psychometric procedures in order to check the correlations and interactions between the psychological and dermatological aspects of the disease. In comparison with a control group, the acne patients did not show any striking endocrinological abnormalities; we found no correlation between the extensiveness of the lesions and the level of DHEA sulphate. All the psychological tests yielded results deviating from those achieved by the representative controls, but they were comparable with those of other patients suffering from psychosomatic diseases. The individual feeling of being "disfigured" found its expression in self-consciousness, lack of trust in his/her own body, as well as the clinically relevant difference between his/her conception of self and the ideal of self. During times of enhanced psychosocial strains subjectively assumed by the patients, the lesions increased and the patients were disturbed in social interaction and communication. Surprisingly, we did not find any correlation between the clinical status and significant psychometric findings. Our results show that in acne vulgaris, the individual experience of wanting physical attractiveness, associated with a predominantly neurotic depressive personal structure, may play a central part in a disturbed process of interaction with the environment and suggest the influence of psychic factors in the pathogenesis of acne vulgaris.

Trustworthiness and relevance in web-based clinical question answering.

PubMed

Cruchet, Sarah; Boyer, Célia; van der Plas, Lonneke

2012-01-01

Question answering systems try to give precise answers to a user's question posed in natural language. It is of utmost importance that the answers returned are relevant to the user's question. For clinical QA, the trustworthiness of answers is another important issue. Limiting the document collection to certified websites helps to improve the trustworthiness of answers. On the other hand, limited document collections are known to harm the relevancy of answers. We show, however, in a comparative evaluation, that promoting trustworthiness has no negative effect on the relevance of the retrieved answers in our clinical QA system. On the contrary, the answers found are in general more relevant.

Mice with reduced NMDA receptor expression: more consistent with autism than schizophrenia?

PubMed

Gandal, M J; Anderson, R L; Billingslea, E N; Carlson, G C; Roberts, T P L; Siegel, S J

2012-08-01

Reduced NMDA-receptor (NMDAR) function has been implicated in the pathophysiology of neuropsychiatric disease, most strongly in schizophrenia but also recently in autism spectrum disorders (ASD). To determine the direct contribution of NMDAR dysfunction to disease phenotypes, a mouse model with constitutively reduced expression of the obligatory NR1 subunit has been developed and extensively investigated. Adult NR1(neo-/-) mice show multiple abnormal behaviors, including reduced social interactions, locomotor hyperactivity, self-injury, deficits in prepulse inhibition (PPI) and sensory hypersensitivity, among others. Whereas such phenotypes have largely been interpreted in the context of schizophrenia, these behavioral abnormalities are rather non-specific and are frequently present across models of diseases characterized by negative symptom domains. This study investigated auditory electrophysiological and behavioral paradigms relevant to autism, to determine whether NMDAR hypofunction may be more consistent with adult ASD-like phenotypes. Indeed, transgenic mice showed behavioral deficits relevant to all core ASD symptoms, including decreased social interactions, altered ultrasonic vocalizations and increased repetitive behaviors. NMDAR disruption recapitulated clinical endophenotypes including reduced PPI, auditory-evoked response N1 latency delay and reduced gamma synchrony. Auditory electrophysiological abnormalities more closely resembled those seen in clinical studies of autism than schizophrenia. These results suggest that NMDAR hypofunction may be associated with a continuum of neuropsychiatric diseases, including schizophrenia and autism. Neural synchrony abnormalities suggest an imbalance of glutamatergic and GABAergic coupling and may provide a target, along with behavioral phenotypes, for preclinical screening of novel therapeutics. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy.

PubMed

Kirk, Jon; Shah, Nirav; Noll, Braxton; Stevens, Craig B; Lawler, Marshall; Mougeot, Farah B; Mougeot, Jean-Luc C

2018-08-01

Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy. Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways. OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM. Our analysis identified 447 genes common to both the "OM" and "wound healing" text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success. Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment.

Metabolic acidosis caused by concomitant use of paracetamol (acetaminophen) and flucloxacillin? A case report and a retrospective study.

PubMed

Berbee, J K; Lammers, L A; Krediet, C T P; Fischer, J C; Kemper, E M

2017-11-01

A patient was identified with severe metabolic acidosis, a high anion gap and 5-oxoproline accumulation, probably caused by the simultaneous use of paracetamol (acetaminophen) and flucloxacillin. We wanted to investigate the necessity to control the interaction between both drugs with an automatic alert system. To investigate the relevance of the interaction of paracetamol and flucloxacillin, a retrospective study was conducted. Data on paracetamol and flucloxacillin prescriptions and laboratory data (pH, Na + , HCO 3 - , Cl - , albumin and 5-oxoproline levels) were combined to assess the prevalence of acidosis, calculate the anion gap and analyse 5-oxoproline levels in clinically admitted patients using both drugs simultaneously. In the 2-year study period, approximately 53,000 admissions took place in our hospital. One thousand and fifty-seven patients used paracetamol and flucloxacillin simultaneously, of which 51 patients (4.8%) had a serum pH ≤ 7.35. One patient, the same patient as presented in the case report, had a high anion gap and a toxic level of 5-oxoproline. The prevalence of metabolic acidosis is very low and the only patient identified with the interaction was recognised during normal clinical care. We conclude that automatic alerts based on simultaneous use of paracetamol and flucloxacillin will generate too many signals. To recognise patients earlier and prevent severe outcomes, a warning system (clinical rule) based on paracetamol, flucloxacillin and pH measurement may be helpful. Early calculation of the anion gap can narrow the differential diagnosis of patients with metabolic acidosis and measurement of 5-oxoproline can explain acidosis due the interaction of paracetamol and flucloxacillin.

Clinical applications of gut microbiota in cancer biology.

PubMed

Wong, Sunny H; Kwong, Thomas N Y; Wu, Chun-Ying; Yu, Jun

2018-05-18

The involvement of microorganisms in cancer has been increasing recognized. Collectively, microorganisms have been estimated to account for ∼20% of all cancers worldwide. Recent advances in metagenomics and bioinformatics have provided new insights on the microbial ecology in different tumors, pinpointing the roles of microorganisms in cancer formation, development and response to treatments. Furthermore, studies have emphasized the importance of host-microbial and inter-microbial interactions in the cancer microbiota. These studies have not only revolutionized our understanding of cancer biology, but also opened up new opportunities for cancer prevention, diagnosis, prognostication and treatment. This review article aims to summarize the microbiota in various cancers and their treatments, and explore clinical applications for such relevance. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

CURRENT CONCEPTS AND TREATMENT OF PATELLOFEMORAL COMPRESSIVE ISSUES.

PubMed

Mullaney, Michael J; Fukunaga, Takumi

2016-12-01

Patellofemoral disorders, commonly encountered in sports and orthopedic rehabilitation settings, may result from dysfunction in patellofemoral joint compression. Osseous and soft tissue factors, as well as the mechanical interaction of the two, contribute to increased patellofemoral compression and pain. Treatment of patellofemoral compressive issues is based on identification of contributory impairments. Use of reliable tests and measures is essential in detecting impairments in hip flexor, quadriceps, iliotibial band, hamstrings, and gastrocnemius flexibility, as well as in joint mobility, myofascial restrictions, and proximal muscle weakness. Once relevant impairments are identified, a combination of manual techniques, instrument-assisted methods, and therapeutic exercises are used to address the impairments and promote functional improvements. The purpose of this clinical commentary is to describe the clinical presentation, contributory considerations, and interventions to address patellofemoral joint compressive issues.

CURRENT CONCEPTS AND TREATMENT OF PATELLOFEMORAL COMPRESSIVE ISSUES

PubMed Central

Fukunaga, Takumi

2016-01-01

Patellofemoral disorders, commonly encountered in sports and orthopedic rehabilitation settings, may result from dysfunction in patellofemoral joint compression. Osseous and soft tissue factors, as well as the mechanical interaction of the two, contribute to increased patellofemoral compression and pain. Treatment of patellofemoral compressive issues is based on identification of contributory impairments. Use of reliable tests and measures is essential in detecting impairments in hip flexor, quadriceps, iliotibial band, hamstrings, and gastrocnemius flexibility, as well as in joint mobility, myofascial restrictions, and proximal muscle weakness. Once relevant impairments are identified, a combination of manual techniques, instrument-assisted methods, and therapeutic exercises are used to address the impairments and promote functional improvements. The purpose of this clinical commentary is to describe the clinical presentation, contributory considerations, and interventions to address patellofemoral joint compressive issues. PMID:27904792

Predictive Suppression of Cortical Excitability and Its Deficit in Schizophrenia

PubMed Central

Schroeder, Charles E.; Leitman, David I.

2013-01-01

Recent neuroscience advances suggest that when interacting with our environment, along with previous experience, we use contextual cues and regularities to form predictions that guide our perceptions and actions. The goal of such active “predictive sensing” is to selectively enhance the processing and representation of behaviorally relevant information in an efficient manner. Since a hallmark of schizophrenia is impaired information selection, we tested whether this deficiency stems from dysfunctional predictive sensing by measuring the degree to which neuronal activity predicts relevant events. In healthy subjects, we established that these mechanisms are engaged in an effort-dependent manner and that, based on a correspondence between human scalp and intracranial nonhuman primate recordings, their main role is a predictive suppression of excitability in task-irrelevant regions. In contrast, schizophrenia patients displayed a reduced alignment of neuronal activity to attended stimuli, which correlated with their behavioral performance deficits and clinical symptoms. These results support the relevance of predictive sensing for normal and aberrant brain function, and highlight the importance of neuronal mechanisms that mold internal ongoing neuronal activity to model key features of the external environment. PMID:23843536

3D facial expression recognition using maximum relevance minimum redundancy geometrical features

NASA Astrophysics Data System (ADS)

Rabiu, Habibu; Saripan, M. Iqbal; Mashohor, Syamsiah; Marhaban, Mohd Hamiruce

2012-12-01

In recent years, facial expression recognition (FER) has become an attractive research area, which besides the fundamental challenges, it poses, finds application in areas, such as human-computer interaction, clinical psychology, lie detection, pain assessment, and neurology. Generally the approaches to FER consist of three main steps: face detection, feature extraction and expression recognition. The recognition accuracy of FER hinges immensely on the relevance of the selected features in representing the target expressions. In this article, we present a person and gender independent 3D facial expression recognition method, using maximum relevance minimum redundancy geometrical features. The aim is to detect a compact set of features that sufficiently represents the most discriminative features between the target classes. Multi-class one-against-one SVM classifier was employed to recognize the seven facial expressions; neutral, happy, sad, angry, fear, disgust, and surprise. The average recognition accuracy of 92.2% was recorded. Furthermore, inter database homogeneity was investigated between two independent databases the BU-3DFE and UPM-3DFE the results showed a strong homogeneity between the two databases.

Eye health programs within remote Aboriginal communities in Australia: a review of the literature.

PubMed

Durkin, Shane R

2008-11-01

To review the literature regarding the most sustainable and culturally appropriate ways in which to implement eye health care programs within remote Aboriginal communities in Australia from a primary health care perspective. The search included letters, editorials and papers (published and unpublished) from January 1955 to April 2006. The search revealed 1,106,758 papers, books and other related material. The relevancy of this material was determined by abstract and 378 relevant articles were reviewed in their entirety. After reading the relevant articles and the interview transcripts the themes that emerged from each source were extracted. The ten areas to consider include: clinical practice and access, sustainability, regional-based programs, information technology systems, health worker training, self-determination, cultural and language barriers, funding body responsibilities, embedding specialist programs in primary care services, and other considerations. Further research needs to be undertaken within Aboriginal communities in the area of primary eye health care and barriers to the acceptance of treatment. This may be undertaken using more interactive research methods such as cooperative and narrative inquiry.

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study.

PubMed

Larkin, S E T; Johnston, H E; Jackson, T R; Jamieson, D G; Roumeliotis, T I; Mockridge, C I; Michael, A; Manousopoulou, A; Papachristou, E K; Brown, M D; Clarke, N W; Pandha, H; Aukim-Hastie, C L; Cragg, M S; Garbis, S D; Townsend, P A

2016-10-25

Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

Biological monitoring of carcinogens: current status and perspectives.

PubMed

Pavanello, Sofia; Lotti, Marcello

2012-04-01

Biomonitoring exposures to carcinogens is common practice and a variety of biomarkers have been developed to assess both exposures and biochemical/biological effects. However, their clinical and preventive relevance is still uncertain. The understanding of cancer as a genetic disease has dramatically evolved during last decades, showing that cancer cell types acquire their characteristics with different strategies, time frames and microenvironments. Therefore, the place of current biomarkers within this complex scenario of gene-environment interactions leading to cancer cannot be defined. Reasons are manifold. Most studies assessed cancer risk on a group basis through snapshots taken at unknown time-points of the postulated chain of events. Little attention has been paid to the variety and variability of exposures, and no prospective study validated the indicators of biochemical/biological effects. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome that combines exposures from all sources both external and internal. The discovery of new biomarkers and the identification of relevant gene-specific pathways could be achieved through metabolomic and genome-wide studies. In conclusion, it is possible to envisage personalized biomonitoring procedures, such as those already implemented in the context of nutrition and clinical oncology.

Microbial colonization and lung function in adolescents with cystic fibrosis.

PubMed

Hector, Andreas; Kirn, Tobias; Ralhan, Anjali; Graepler-Mainka, Ute; Berenbrinker, Sina; Riethmueller, Joachim; Hogardt, Michael; Wagner, Marlies; Pfleger, Andreas; Autenrieth, Ingo; Kappler, Matthias; Griese, Matthias; Eber, Ernst; Martus, Peter; Hartl, Dominik

2016-05-01

With intensified antibiotic therapy and longer survival, patients with cystic fibrosis (CF) are colonized with a more complex pattern of bacteria and fungi. However, the clinical relevance of these emerging pathogens for lung function remains poorly defined. The aim of this study was to assess the association of bacterial and fungal colonization patterns with lung function in adolescent patients with CF. Microbial colonization patterns and lung function parameters were assessed in 770 adolescent European (German/Austrian) CF patients in a retrospective study (median follow-up time: 10years). Colonization with Pseudomonas aeruginosa and MRSA were most strongly associated with loss of lung function, while mainly colonization with Haemophilus influenzae was associated with preserved lung function. Aspergillus fumigatus was the only species that was associated with an increased risk for infection with P. aeruginosa. Microbial interaction analysis revealed three distinct microbial clusters within the longitudinal course of CF lung disease. Collectively, this study identified potentially protective and harmful microbial colonization patterns in adolescent CF patients. Further studies in different patient cohorts are required to evaluate these microbial patterns and to assess their clinical relevance. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Perspectives of gene expression profiling for diagnosis and therapy in haematological malignancies.

PubMed

Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

2009-05-01

Considering the heterogeneity of leukaemias and the widening spectrum of therapeutic strategies, novel diagnostic methods are urgently needed for haematological malignancies. For a decade, gene expression profiling (GEP) has been applied in leukaemia research. Thus, various studies demonstrated worldwide that the majority of genetically defined leukaemia subtypes are accurately predictable by GEP, for example, with respect to reciprocal rearrangements in acute myeloid leukaemia (AML). Moreover, novel prognostically relevant gene classifiers were developed as, for example, in normal karyotype AML. Considering the lymphatic malignancies, GEP studies defined novel clinically relevant subtypes in diffuse large B cell lymphoma (DLBCL), and improved the discrimination of Burkitt lymphoma and DLBCL cases, overcoming considerable overlaps of these entities that exist from morphological and genetic perspectives. Treatment-specific sensitivity assays are being developed for targeted drugs such as farnesyl transferase inhibitors in AML or imatinib in BCR-ABL1 positive acute lymphoblastic leukaemia (ALL). Irrespectively of these proceedings, an introduction of the microarray technology in haematological practice requires diagnostic algorithms and strategies for interaction with currently established diagnostic techniques. Large multicentre studies such as the MILE Study (Microarray Innovations in LEukemia) aim at translating this methodology into clinical routine workflows and to catalyze this process.

Psychiatric disorders as vulnerability factors for nicotine addiction: what have we learned from animal models?

PubMed

Le Foll, Bernard; Ng, Enoch; Di Ciano, Patricia; Trigo, José M

2015-01-01

Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatric disorders. Notably, there is a high prevalence of smoking among those with dependence to other substances, schizophrenia, mood, or anxiety disorders. It has been difficult to understand how these phenomena interact with clinical populations as it is unclear what preceded what in most of the studies. These comorbidities may be best understood by using experimental approaches in well-controlled conditions. Notably, animal models represent advantageous approaches as the parameters under study can be controlled perfectly. This review will focus on evidence collected so far exploring how behavioral effects of nicotine are modified in animal models of psychiatric conditions. Notably, we will focus on behavioral responses induced by nicotine that are relevant for its addictive potential. Despite the clinical relevance and frequency of the comorbidity between psychiatric issues and tobacco smoking, very few studies have been done to explore this issue in animals. The available data suggest that the behavioral and reinforcing effects of nicotine are enhanced in animal models of these comorbidities, although much more experimental work would be required to provide certainty in this domain.

Practice, science and governance in interaction: European effort for the system-wide implementation of the International Classification of Functioning, Disability and Health (ICF) in Physical and Rehabilitation Medicine.

PubMed

Stucki, Gerold; Zampolini, Mauro; Juocevicius, Alvydas; Negrini, Stefano; Christodoulou, Nicolas

2017-04-01

Since its launch in 2001, relevant international, regional and national PRM bodies have aimed to implement the International Classification of Functioning, Disability and Health (ICF) in Physical and Rehabilitation Medicine (PRM), whereby contributing to the development of suitable practical tools. These tools are available for implementing the ICF in day-to-day clinical practice, standardized reporting of functioning outcomes in quality management and research, and guiding evidence-informed policy. Educational efforts have reinforced PRM physicians' and other rehabilitation professionals' ICF knowledge, and numerous implementation projects have explored how the ICF is applied in clinical practice, research and policy. Largely lacking though is the system-wide implementation of ICF in day-to-day practice across all rehabilitation services of national health systems. In Europe, system-wide implementation of ICF requires the interaction between practice, science and governance. Considering its mandate, the UEMS PRM Section and Board have decided to lead a European effort towards system-wide ICF implementation in PRM, rehabilitation and health care at large, in interaction with governments, non-governmental actors and the private sector, and aligned with ISPRM's collaboration plan with WHO. In this paper we present the current PRM internal and external policy agenda towards system-wide ICF implementation and the corresponding implementation action plan, while highlighting priority action steps - promotion of ICF-based standardized reporting in national quality management and assurance programs, development of unambiguous rehabilitation service descriptions using the International Classification System for Service Organization in Health-related Rehabilitation, development of Clinical Assessment Schedules, qualitative linkage and quantitative mapping of data to the ICF, and the cultural adaptation of the ICF Clinical Data Collection Tool in European languages.

Live attenuated influenza virus increases pneumococcal translocation and persistence within the middle ear.

PubMed

Mina, Michael J; Klugman, Keith P; Rosch, Jason W; McCullers, Jonathan A

2015-07-15

Infection with influenza A virus (IAV) increases susceptibility to respiratory bacterial infections, resulting in increased bacterial carriage and complications such acute otitis media, pneumonia, bacteremia, and meningitis. Recently, vaccination with live attenuated influenza virus (LAIV) was reported to enhance subclinical bacterial colonization within the nasopharynx, similar to IAV. Although LAIV does not predispose to bacterial pneumonia, whether it may alter bacterial transmigration toward the middle ear, where it could have clinically relevant implications, has not been investigated. BALB/c mice received LAIV or phosphate-buffered saline 1 or 7 days before or during pneumococcal colonization with either of 2 clinical isolates, 19F or 7F. Middle ear bacterial titers were monitored daily via in vivo imaging. LAIV increased bacterial transmigration to and persistence within the middle ear. When colonization followed LAIV inoculation, a minimum LAIV incubation period of 4 days was required before bacterial transmigration commenced. While LAIV vaccination is safe and effective at reducing IAV and coinfection with influenza virus and bacteria, LAIV may increase bacterial transmigration to the middle ear and could thus increase the risk of clinically relevant acute otitis media. These data warrant further investigations into interactions between live attenuated viruses and naturally colonizing bacterial pathogens. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Factors influencing adherence to psychopharmacological medications in psychiatric patients: a structural equation modeling approach.

PubMed

De Las Cuevas, Carlos; de Leon, Jose; Peñate, Wenceslao; Betancort, Moisés

2017-01-01

To evaluate pathways through which sociodemographic, clinical, attitudinal, and perceived health control variables impact psychiatric patients' adherence to psychopharmacological medications. A sample of 966 consecutive psychiatric outpatients was studied. The variables were sociodemographic (age, gender, and education), clinical (diagnoses, drug treatment, and treatment duration), attitudinal (attitudes toward psychopharmacological medication and preferences regarding participation in decision-making), perception of control over health (health locus of control, self-efficacy, and psychological reactance), and level of adherence to psychopharmacological medications. Structural equation modeling was applied to examine the nonstraightforward relationships and the interactive effects among the analyzed variables. Structural equation modeling demonstrated that psychiatric patients' treatment adherence was associated: 1) negatively with cognitive psychological reactance (adherence decreased as cognitive psychological reactance increased), 2) positively with patients' trust in their psychiatrists (doctors' subscale), 3) negatively with patients' belief that they are in control of their mental health and that their mental health depends on their own actions (internal subscale), and 4) positively (although weakly) with age. Self-efficacy indirectly influenced treatment adherence through internal health locus of control. This study provides support for the hypothesis that perceived health control variables play a relevant role in psychiatric patients' adherence to psychopharmacological medications. The findings highlight the importance of considering prospective studies of patients' psychological reactance and health locus of control as they may be clinically relevant factors contributing to adherence to psychopharmacological medications.

Bayesian Weibull tree models for survival analysis of clinico-genomic data

PubMed Central

Clarke, Jennifer; West, Mike

2008-01-01

An important goal of research involving gene expression data for outcome prediction is to establish the ability of genomic data to define clinically relevant risk factors. Recent studies have demonstrated that microarray data can successfully cluster patients into low- and high-risk categories. However, the need exists for models which examine how genomic predictors interact with existing clinical factors and provide personalized outcome predictions. We have developed clinico-genomic tree models for survival outcomes which use recursive partitioning to subdivide the current data set into homogeneous subgroups of patients, each with a specific Weibull survival distribution. These trees can provide personalized predictive distributions of the probability of survival for individuals of interest. Our strategy is to fit multiple models; within each model we adopt a prior on the Weibull scale parameter and update this prior via Empirical Bayes whenever the sample is split at a given node. The decision to split is based on a Bayes factor criterion. The resulting trees are weighted according to their relative likelihood values and predictions are made by averaging over models. In a pilot study of survival in advanced stage ovarian cancer we demonstrate that clinical and genomic data are complementary sources of information relevant to survival, and we use the exploratory nature of the trees to identify potential genomic biomarkers worthy of further study. PMID:18618012

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

PubMed Central

Norris, John D.; Ellison, Stephanie J.; Baker, Jennifer G.; Stagg, David B.; Wardell, Suzanne E.; Park, Sunghee; Alley, Holly M.; Baldi, Robert M.; Yllanes, Alexander; Andreano, Kaitlyn J.; Stice, James P.; Lawrence, Scott A.; Eisner, Joel R.; Price, Douglas K.; Moore, William R.; Figg, William D.; McDonnell, Donald P.

2017-01-01

The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase–selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel’s direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor–bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC. PMID:28463227

'The Loss of My Elderly Patient:' Interactive reflective writing to support medical students' rites of passage.

PubMed

Wald, Hedy S; Reis, Shmuel P; Monroe, Alicia D; Borkan, Jeffrey M

2010-01-01

The fostering of reflective capacity within medical education helps develop critical thinking and clinical reasoning skills and enhances professionalism. Use of reflective narratives to augment reflective practice instruction is well documented. At Warren Alpert Medical School of Brown University (Alpert Med), a narrative medicine curriculum innovation of students' reflective writing (field notes) with individualized feedback from an interdisciplinary faculty team (in pre-clinical years) has been implemented in a Doctoring course to cultivate reflective capacity, empathy, and humanism. Interactive reflective writing (student writer/faculty feedback provider dyad), we propose, can additionally support students with rites of passage at critical educational junctures. At Alpert Med, we have devised a tool to guide faculty in crafting quality feedback, i.e. the Brown Educational Guide to Analysis of Narrative (BEGAN) which includes identifying students' salient quotes, utilizing reflection-inviting questions and close reading, highlighting derived lessons/key concepts, extracting clinical patterns, and providing concrete recommendations as relevant. We provide an example of a student's narrative describing an emotionally powerful and meaningful event - the loss of his first patient - and faculty responses using BEGAN. The provision of quality feedback to students' reflective writing - supported by BEGAN - can facilitate the transformation of student to professional through reflection within medical education.

Making medical decisions in dependence of genetic background: estimation of the utility of DNA testing in clinical, pharmaco-epidemiological or genetic studies.

PubMed

Nguyen, Thuy Trang; Schäfer, Helmut; Timmesfeld, Nina

2013-05-01

An index measuring the utility of testing a DNA marker before deciding between two alternative treatments is proposed which can be estimated from pharmaco-epidemiological case-control or cohort studies. In the case-control design, external estimates of the prevalence of the disease and of the frequency of the genetic risk variant are required for estimating the utility index. Formulas for point and interval estimates are derived. Empirical coverage probabilities of the confidence intervals were estimated under different scenarios of disease prevalence, prevalence of drug use, and population frequency of the genetic variant. To illustrate our method, we re-analyse pharmaco-epidemiological case-control data on oral contraceptive intake and venous thrombosis in carriers and non-carriers of the factor V Leiden mutation. We also re-analyse cross-sectional data from the Framingham study on a gene-diet interaction between an APOA2 polymorphism and high saturated fat intake on obesity. We conclude that the utility index may be helpful to evaluate and appraise the potential clinical and public health relevance of gene-environment interaction effects detected in genomic and candidate gene association studies and may be a valuable decision support for designing prospective studies on the clinical utility. © 2013 Wiley Periodicals, Inc.

Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

PubMed

Goto, Shinya; Zhu, Jun; Liu, Lisheng; Oh, Byung-Hee; Wojdyla, Daniel M; Aylward, Philip; Bahit, M Cecilia; Gersh, Bernard J; Hanna, Michael; Horowitz, John; Lopes, Renato D; Wallentin, Lars; Xavier, Denis; Alexander, John H

2014-09-01

The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation are unknown. ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio [HR] 0.74, 95% CI 0.50-1.10) and non-East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non-East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non-East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia. Copyright © 2014 Mosby, Inc. All rights reserved.

Motor-visual neurons and action recognition in social interactions.

PubMed

de la Rosa, Stephan; Bülthoff, Heinrich H

2014-04-01

Cook et al. suggest that motor-visual neurons originate from associative learning. This suggestion has interesting implications for the processing of socially relevant visual information in social interactions. Here, we discuss two aspects of the associative learning account that seem to have particular relevance for visual recognition of social information in social interactions - namely, context-specific and contingency based learning.

Reflections on relevance: Psychotherapy and Psychosomatics in 2004.

PubMed

Balon, Richard

2005-01-01

Relevance of an article is a highly desirable yet hardly predictable quality at the time of its publication. Article relevance is frequently measured by the impact factor of the journal where the article is published. Furthermore, impact factor, citation index and citation analysis are used as a measure of research progress and scientific wealth of a nation. The wisdom and significance of this approach to relevance is debatable and thus discussed here. In 2004, Psychotherapy and Psychosomatics published a variety of articles which, in the author's view, are clinically relevant. Several selected clinically relevant issues reviewed in this article include: the conceptualization of fibromyalgia as a stress disorder; the psychosocial impact and psychosocial interventions in cancer; the impact of alexithymia on patient care; the possible relationship between depression and nutrition (namely intake of folate and pyridoxal phosphate); the significance of hypercoagulability in panic-like anxiety; the questionable value of single isomer drugs, and the relevance and adequacy of clinimetrics versus psychometrics in clinical research. The reviewed issues seem to be relevant to clinical practice, research or both, but also to our critical thinking, and the critical review of the developments in psychiatry and psychology. Copyright 2005 S. Karger AG, Basel.

Food-Drug Interactions

PubMed Central

Bushra, Rabia; Aslam, Nousheen; Khan, Arshad Yar

2011-01-01

The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least food-drug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient. PMID:22043389

Content validation: clarity/relevance, reliability and internal consistency of enunciative signs of language acquisition.

PubMed

Crestani, Anelise Henrich; Moraes, Anaelena Bragança de; Souza, Ana Paula Ramos de

2017-08-10

To analyze the results of the validation of building enunciative signs of language acquisition for children aged 3 to 12 months. The signs were built based on mechanisms of language acquisition in an enunciative perspective and on clinical experience with language disorders. The signs were submitted to judgment of clarity and relevance by a sample of six experts, doctors in linguistic in with knowledge of psycholinguistics and language clinic. In the validation of reliability, two judges/evaluators helped to implement the instruments in videos of 20% of the total sample of mother-infant dyads using the inter-evaluator method. The method known as internal consistency was applied to the total sample, which consisted of 94 mother-infant dyads to the contents of the Phase 1 (3-6 months) and 61 mother-infant dyads to the contents of Phase 2 (7 to 12 months). The data were collected through the analysis of mother-infant interaction based on filming of dyads and application of the parameters to be validated according to the child's age. Data were organized in a spreadsheet and then converted to computer applications for statistical analysis. The judgments of clarity/relevance indicated no modifications to be made in the instruments. The reliability test showed an almost perfect agreement between judges (0.8 ≤ Kappa ≥ 1.0); only the item 2 of Phase 1 showed substantial agreement (0.6 ≤ Kappa ≥ 0.79). The internal consistency for Phase 1 had alpha = 0.84, and Phase 2, alpha = 0.74. This demonstrates the reliability of the instruments. The results suggest adequacy as to content validity of the instruments created for both age groups, demonstrating the relevance of the content of enunciative signs of language acquisition.

Mechanisms for pattern specificity of deep-brain stimulation in Parkinson’s disease

PubMed Central

Mato, Germán; Dellavale, Damián

2017-01-01

Deep brain stimulation (DBS) has become a widely used technique for treating advanced stages of neurological and psychiatric illness. In the case of motor disorders related to basal ganglia (BG) dysfunction, several mechanisms of action for the DBS therapy have been identified which might be involved simultaneously or in sequence. However, the identification of a common key mechanism underlying the clinical relevant DBS configurations has remained elusive due to the inherent complexity related to the interaction between the electrical stimulation and the neural tissue, and the intricate circuital structure of the BG-thalamocortical network. In this work, it is shown that the clinically relevant range for both, the frequency and intensity of the electrical stimulation pattern, is an emergent property of the BG anatomy at the system-level that can be addressed using mean-field descriptive models of the BG network. Moreover, it is shown that the activity resetting mechanism elicited by electrical stimulation provides a natural explanation to the ineffectiveness of irregular (i.e., aperiodic) stimulation patterns, which has been commonly observed in previously reported pathophysiology models of Parkinson’s disease. Using analytical and numerical techniques, these results have been reproduced in both cases: 1) a reduced mean-field model that can be thought as an elementary building block capable to capture the underlying fundamentals of the relevant loops constituting the BG-thalamocortical network, and 2) a detailed model constituted by the direct and hyperdirect loops including one-dimensional spatial structure of the BG nuclei. We found that the optimal ranges for the essential parameters of the stimulation patterns can be understood without taking into account biophysical details of the relevant structures. PMID:28813460

Diagnostic value of clinical tests for degenerative rotator cuff disease in medical practice.

PubMed

Lasbleiz, S; Quintero, N; Ea, K; Petrover, D; Aout, M; Laredo, J D; Vicaut, E; Bardin, T; Orcel, P; Beaudreuil, J

2014-06-01

To assess the diagnostic value of clinical tests for degenerative rotator cuff disease (DRCD) in medical practice. Patients with DRCD were prospectively included. Eleven clinical tests of the rotator cuff have been done. One radiologist performed ultrasonography (US) of the shoulder. Results of US were expressed as normal tendon, tendinopathy or full-thickness tear (the reference). For each clinical test and each US criteria, sensitivity, specificity, negative predictive value and positive predictive value, accuracy, negative likelihood ratio (NLR) and positive likelihood ratio (PLR) were calculated. Clinical relevance was defined as PLR ≥2 and NLR ≤0.5. For 35 patients (39 shoulders), Jobe (PLR: 2.08, NLR: 0.31) and full-can (2, 0.5) test results were relevant for diagnosis of supraspinatus tears and resisted lateral rotation (2.42, 0.5) for infraspinatus tears, with weakness as response criteria. The lift-off test (8.50, 0.27) was relevant for subscapularis tears with lag sign as response criteria. Yergason's test (3.7, 0.41) was relevant for tendinopathy of the long head of the biceps with pain as a response criterion. There was no relevant clinical test for diagnosis of tendinopathy of supraspinatus, infraspinatus or subscapularis. Five of 11 clinical tests were relevant for degenerative rotator cuff disease. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors.

PubMed

Gabardi, Steven; Olyaei, Ali

2012-01-01

To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity does not impact EC-MPA and bioavailability is maintained with this formulation during PPI coadministration. The clinical impact of this interaction is unknown, yet one can theorize that reduced exposure to MPA in SOT recipients can increase the risk of allograft rejection and/or failure.

Short-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase Associates with a Protein Super-Complex Integrating Multiple Metabolic Pathways

PubMed Central

Narayan, Srinivas B.; Master, Stephen R.; Sireci, Anthony N.; Bierl, Charlene; Stanley, Paige E.; Li, Changhong; Stanley, Charles A.; Bennett, Michael J.

2012-01-01

Proteins involved in mitochondrial metabolic pathways engage in functionally relevant multi-enzyme complexes. We previously described an interaction between short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) and glutamate dehydrogenase (GDH) explaining the clinical phenotype of hyperinsulinism in SCHAD-deficient patients and adding SCHAD to the list of mitochondrial proteins capable of forming functional, multi-pathway complexes. In this work, we provide evidence of SCHAD's involvement in additional interactions forming tissue-specific metabolic super complexes involving both membrane-associated and matrix-dwelling enzymes and spanning multiple metabolic pathways. As an example, in murine liver, we find SCHAD interaction with aspartate transaminase (AST) and GDH from amino acid metabolic pathways, carbamoyl phosphate synthase I (CPS-1) from ureagenesis, other fatty acid oxidation and ketogenesis enzymes and fructose-bisphosphate aldolase, an extra-mitochondrial enzyme of the glycolytic pathway. Most of the interactions appear to be independent of SCHAD's role in the penultimate step of fatty acid oxidation suggesting an organizational, structural or non-enzymatic role for the SCHAD protein. PMID:22496890

In silico Driven Redesign of a Clinically Relevant Antibody for the Treatment of GD2 Positive Tumors

PubMed Central

Ahmed, Mahiuddin; Goldgur, Yehuda; Hu, Jian; Guo, Hong-Fen; Cheung, Nai-Kong V.

2013-01-01

Ganglioside GD2 is a cell surface glycolipid that is highly expressed on cancer cells of neuroectodermal origin, including neuroblastoma, retinoblastoma, melanoma, sarcomas, brain tumors and small cell lung cancer. Monoclonal antibodies (MoAb) that target GD2 have shown clinical efficacy in the treatment of GD2 expressing tumors, and are expected to be the new standard of care for the treatment of pediatric neuroblastoma. In this study, the crystal structure of anti-GD2 murine MoAb 3F8 was solved to 1.65 Å resolution and used as a template for molecular docking simulations of its antigen, the penta-saccharide head group of GD2. Molecular docking revealed a binding motif composed of 12 key interacting amino acid side-chains, involving an extensive network of interactions involving main-chain and side-chain hydrogen bonding, two Pi – CH interactions, and an important charged interaction between Arg95 of the H3 loop with the penultimate sialic acid residue of GD2. Based on in silico scanning mutagenesis of the 12 interacting amino acids from the docked 3F8:GD2 model, a single point mutation (Heavy Chain: Gly54Ile) was engineered into a humanized 3F8 (hu3F8) MoAb and found to have a 6–9 fold enhancement in antibody-dependent cell-mediated cytotoxicity of neuroblastoma and melanoma cell lines. With enhanced tumor-killing properties, the re-engineered hu3F8 has the potential be a more effective antibody for the treatment of GD2-positive tumors. PMID:23696816

Interactive effect of negative affectivity and anxiety sensitivity in terms of mental health among Latinos in primary care.

PubMed

Zvolensky, Michael J; Paulus, Daniel J; Bakhshaie, Jafar; Garza, Monica; Ochoa-Perez, Melissa; Medvedeva, Angela; Bogiaizian, Daniel; Robles, Zuzuky; Manning, Kara; Schmidt, Norman B

2016-09-30

From a public health perspective, primary care medical settings represent a strategic location to address mental health disapirty among Latinos. Yet, there is little empirical work that addresses affective vulnerability processes for mental health problems in such settings. To help address this gap in knowledge, the present investigation examined an interactive model of negative affectivity (tendency to experience negative mood states) and anxiety sensitivity (fear of the negative consequences of aversive sensations) among a Latino sample in primary care in terms of a relatively wide range of anxiety/depression indices. Participants included 390 Latino adults (Mage=38.7, SD=11.3; 86.9% female; 95.6% reported Spanish as first language) from a primary care health clinic. Primary dependent measures included depressive, suicidal, social anxiety, and anxious arousal symptoms, number of mood and anxiety disorders, and disability. Consistent with prediction, the interaction between negative affectivity and anxiety sensitivity was significantly related to suicidal, social anxiety, and anxious arousal symptoms, as well as number of mood/anxiety diagnoses and disability among the primary care Latino sample. The form of the interactions indicated a synergistic effect, such that the greatest levels of each outcome were found among those with high negative affectivity and high anxiety sensitivity. There was a trending interaction for depressive symptoms. Overall, these data provide novel empirical evidence suggesting that there is a clinically-relevant interplay between anxiety sensitivity and negative affectivity in regard to the expression of anxiety and depressive symptoms among a Latino primary care sample. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Retrieval of diagnostic and treatment studies for clinical use through PubMed and PubMed's Clinical Queries filters.

PubMed

Lokker, Cynthia; Haynes, R Brian; Wilczynski, Nancy L; McKibbon, K Ann; Walter, Stephen D

2011-01-01

Clinical Queries filters were developed to improve the retrieval of high-quality studies in searches on clinical matters. The study objective was to determine the yield of relevant citations and physician satisfaction while searching for diagnostic and treatment studies using the Clinical Queries page of PubMed compared with searching PubMed without these filters. Forty practicing physicians, presented with standardized treatment and diagnosis questions and one question of their choosing, entered search terms which were processed in a random, blinded fashion through PubMed alone and PubMed Clinical Queries. Participants rated search retrievals for applicability to the question at hand and satisfaction. For treatment, the primary outcome of retrieval of relevant articles was not significantly different between the groups, but a higher proportion of articles from the Clinical Queries searches met methodologic criteria (p=0.049), and more articles were published in core internal medicine journals (p=0.056). For diagnosis, the filtered results returned more relevant articles (p=0.031) and fewer irrelevant articles (overall retrieval less, p=0.023); participants needed to screen fewer articles before arriving at the first relevant citation (p<0.05). Relevance was also influenced by content terms used by participants in searching. Participants varied greatly in their search performance. Clinical Queries filtered searches returned more high-quality studies, though the retrieval of relevant articles was only statistically different between the groups for diagnosis questions. Retrieving clinically important research studies from Medline is a challenging task for physicians. Methodological search filters can improve search retrieval.

"We're Friends, We Have to Be in This Together": Examining the Role of Culturally Relevant Peer Interactions in Urban Youth's College Readiness and Access

ERIC Educational Resources Information Center

Marciano, Joanne E.

2017-01-01

This paper analyzes how and why ten Black and Latina/o youth attending an urban public high school engage culturally relevant peer interactions (Knight and Marciano in "College ready: preparing Black and Latina/o youth for higher education--a culturally relevant approach." Teachers College Press, New York, 2013) in preparing for,…

Clinical relevance of diagnosing COPD by fixed ratio or lower limit of normal: a systematic review.

PubMed

van Dijk, Wouter D; Gupta, Nisha; Tan, Wan C; Bourbeau, Jean

2014-02-01

Different spirometric criteria in diagnosing COPD have been advocated by different groups, debilitating adequate diagnosis and treatment of COPD. We reviewed the clinical relevance of fixed ratio and lower limit of normal (LLN) in diagnosing COPD and explored if modifying factors may affect their clinical relevance. Two reviewers independently searched PubMed and Embase for papers that compared both criteria on any clinically relevant outcome, published before June 1st, 2012, without any language restriction. Two reviewers independently extracted the study characteristics, including study design, population characteristics and diagnostic criteria used, and summarized the results of clinical relevance. Study quality was assessed by scoring forms for bias and level of evidence. Of 394 studies retrieved, 11 studies were included, with a median of 1,258 participants. Although both criteria appeared related with various clinically relevant outcomes, we were unable to prefer one criterion over the other, with various performances of the criteria for different outcomes. Should the criteria disagree on diagnosis, an alternative diagnosis should be suspected, in particular in those (elderly) with less severe airflow limitation for whom the LLN appears a better criterion. The fixed ratio appears to perform better in subjects with more severe airflow limitation. In diagnosing COPD, severity of airflow limitation appears an important factor for choosing whether the fixed ratio or LLN. Disagreement between the criteria is suggestive for an alternative diagnosis. Future studies on clinical relevance should further reveal the criterion of choice, in order to improve adequate diagnosis and consequent treatments.

PPARγ and its ligands: therapeutic implications in cardiovascular disease

PubMed Central

Villacorta, Luis; Schopfer, Francisco J.; Zhang, Jifeng; Freeman, Bruce A.; Chen, Y. Eugene

2009-01-01

The relevance of peroxisome proliferator-activated receptor-γ (PPARγ) as an important therapeutic target for the treatment of diabetes arises from its hypoglycemic effects in diabetic patients and also from the critical role in the regulation of cardiovascular functions. From a clinical perspective, differences between currently FDA-approved PPARγ drugs have been observed in terms of atherosclerosis, cardiac and stroke events. The adverse effects of PPARγ-specific treatments that hamper their cardiovascular protective roles, affirm the strong need to evaluate the efficacy of the current drugs. Therefore, active research is directed towards high-throughput screening and pharmacologic testing of a plethora of newly identified natural or synthetic compounds. Here we describe the rationale behind drug design strategies targeting PPARγ, based on current knowledge regarding the effects of such drugs in experimental animal models as well as in the clinical practice. Regarding endogenous PPARγ ligands, several fatty acid derivatives bind PPARγ with different affinity, though the physiological relevance of these interactions is not always evident. Recently, nitric oxide-derived unsaturated fatty acids were found to be potent agonists of PPARs, with preferential affinity for PPARγ, compared to oxidized fatty acid derivatives. Nitroalkenes exert important bioactivities of relevance for the cardiovascular system including anti-inflammatory and anti-platelet actions and are important mediators of vascular tone. A new generation of insulin sensitizers with PPARγ function for the treatment of diabetes, may serve to limit patients from the increased cardiovascular burden of this disease. PMID:19118492

Novel entries in a fungal biofilm matrix encyclopedia.

PubMed

Zarnowski, Robert; Westler, William M; Lacmbouh, Ghislain Ade; Marita, Jane M; Bothe, Jameson R; Bernhardt, Jörg; Lounes-Hadj Sahraoui, Anissa; Fontaine, Joël; Sanchez, Hiram; Hatfield, Ronald D; Ntambi, James M; Nett, Jeniel E; Mitchell, Aaron P; Andes, David R

2014-08-05

Virulence of Candida is linked with its ability to form biofilms. Once established, biofilm infections are nearly impossible to eradicate. Biofilm cells live immersed in a self-produced matrix, a blend of extracellular biopolymers, many of which are uncharacterized. In this study, we provide a comprehensive analysis of the matrix manufactured by Candida albicans both in vitro and in a clinical niche animal model. We further explore the function of matrix components, including the impact on drug resistance. We uncovered components from each of the macromolecular classes (55% protein, 25% carbohydrate, 15% lipid, and 5% nucleic acid) in the C. albicans biofilm matrix. Three individual polysaccharides were identified and were suggested to interact physically. Surprisingly, a previously identified polysaccharide of functional importance, β-1,3-glucan, comprised only a small portion of the total matrix carbohydrate. Newly described, more abundant polysaccharides included α-1,2 branched α-1,6-mannans (87%) associated with unbranched β-1,6-glucans (13%) in an apparent mannan-glucan complex (MGCx). Functional matrix proteomic analysis revealed 458 distinct activities. The matrix lipids consisted of neutral glycerolipids (89.1%), polar glycerolipids (10.4%), and sphingolipids (0.5%). Examination of matrix nucleic acid identified DNA, primarily noncoding sequences. Several of the in vitro matrix components, including proteins and each of the polysaccharides, were also present in the matrix of a clinically relevant in vivo biofilm. Nuclear magnetic resonance (NMR) analysis demonstrated interaction of aggregate matrix with the antifungal fluconazole, consistent with a role in drug impedance and contribution of multiple matrix components. Importance: This report is the first to decipher the complex and unique macromolecular composition of the Candida biofilm matrix, demonstrate the clinical relevance of matrix components, and show that multiple matrix components are needed for protection from antifungal drugs. The availability of these biochemical analyses provides a unique resource for further functional investigation of the biofilm matrix, a defining trait of this lifestyle. Copyright © 2014 Zarnowski et al.

[Emotional burnout syndrome and pedagogical styles in teachers of a medical high school].

PubMed

Ivanova, E I; Ivanov, I V; Serdakova, K G

2011-01-01

The study involved 20 teachers of medical institutions who gave consent to be examined for emotional burnout syndrome (EBS). Diagnosis of moderate EBS was confirmed by relevant clinical tests and analysis of pedagogical communication style in 30% of the participants. The pedagogical style of teachers exhibiting no signs of burnout is characterized by personality-oriented model of communication with differential attitudes toward students and active interaction with them. Teachers presenting with EBS relied on the disciplinary model of communication prevailed by authoritarian and dictatorial behaviour lacking communicability and flexibility; these persons showed pronounced hyperreflexia.

Bioreactor engineering of stem cell environments.

PubMed

Tandon, Nina; Marolt, Darja; Cimetta, Elisa; Vunjak-Novakovic, Gordana

2013-11-15

Stem cells hold promise to revolutionize modern medicine by the development of new therapies, disease models and drug screening systems. Standard cell culture systems have limited biological relevance because they do not recapitulate the complex 3-dimensional interactions and biophysical cues that characterize the in vivo environment. In this review, we discuss the current advances in engineering stem cell environments using novel biomaterials and bioreactor technologies. We also reflect on the challenges the field is currently facing with regard to the translation of stem cell based therapies into the clinic. Copyright © 2013 Elsevier Inc. All rights reserved.

Herb-drug interaction: a case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit.

PubMed

Okonta, J M; Uboh, M; Obonga, W O

2008-01-01

The effect of ginger on the pharmacokinectic of metronidazole was studied using rabbits in a crossover study method. The relevance of this study borders on the wide use of ginger for culinary and phytotherapeutic purposes, and metronidazole that is commonly used for every gastrointestinal complain in our communities without prescription. Ginger significantly increased the absorption and plasma half-life, and significantly decreased the elimination rate constant and clearance of metronidazole (P<0.05). Thus, in clinical practice, the patients should be advised on the serious implication of using both items together.

TAM receptors in apoptotic cell clearance, autoimmunity, and cancer.

PubMed

Nguyen, Khanh-Quynh; Tsou, Wen-I; Kotenko, Sergei; Birge, Raymond B

2013-08-01

Receptor tyrosine kinases, Tyro-3, Axl and Mer, collectively designated as TAM, are involved in the clearance of apoptotic cells. TAM ligands, Gas6 and Protein S, bind to the surfaces of apoptotic cells, and at the same time, interact directly with TAM expressed on phagocytes, impacting the engulfment and clearance of apoptotic cells and debris. The well-tuned and balanced actions of TAM may affect a variety of human pathologies including autoimmunity, retinal degeneration, and cancer. This article emphasizes some of the emerging findings and mechanistic insights into TAM functions that are clinically relevant and possibly therapeutically targeted.

Insights from clinical research completed during the west Africa Ebola virus disease epidemic

PubMed Central

Rojek, Amanda; Horby, Peter; Dunning, Jake

2018-01-01

The west Africa Ebola virus disease (EVD) epidemic was extraordinary in scale. Now that the epidemic has ended, it is a relevant time to examine published studies with direct relevance to clinical care and, more broadly, to examine the implications of the clinical research response mounted. Clinically relevant research includes literature detailing risk factors for and clinical manifestations of EVD, laboratory and other investigation findings in patients, experimental vaccine and therapeutic clinical trials, and analyses of survivor syndrome. In this Review, we discuss new insights from patient-oriented research completed during the west Africa epidemic, identify ongoing knowledge gaps, and suggest priorities for future research. PMID:28461209

Everyday ethics in internal medicine resident clinic: an opportunity to teach.

PubMed

Carrese, Joseph A; McDonald, Erin L; Moon, Margaret; Taylor, Holly A; Khaira, Kiran; Catherine Beach, Mary; Hughes, Mark T

2011-07-01

Being a good doctor requires competency in ethics. Accordingly, ethics education during residency training is important. We studied the everyday ethics-related issues (i.e. ordinary ethics issues commonly faced) that internal medical residents encounter in their out-patient clinic and determined whether teaching about these issues occurred during faculty preceptor-resident interactions. This study involved a multi-method qualitative research design combining observation of preceptor-resident discussions with preceptor interviews. The study was conducted in two different internal medicine training programme clinics over a 2-week period in June 2007. Fifty-three residents and 19 preceptors were observed, and 10 preceptors were interviewed. Transcripts of observer field notes and faculty interviews were carefully analysed. The analysis identified several themes of everyday ethics issues and determined whether preceptors identified and taught about these issues. Everyday ethics content was considered present in 109 (81%) of the 135 observed case presentations. Three major thematic domains and associated sub-themes related to everyday ethics issues were identified, concerning: (i) the Doctor-Patient Interaction (relationships; communication; shared decision making); (ii) the Resident as Learner (developmental issues; challenges and conflicts associated with training; relationships with colleagues and mentors; interactions with the preceptor), and; (iii) the Doctor-System Interaction (financial issues; doctor-system issues; external influences; doctor frustration related to system issues). Everyday ethics issues were explicitly identified by preceptors (without teaching) in 18 of 109 cases (17%); explicit identification and teaching occurred in only 13 cases (12%). In this study a variety of everyday ethics issues were frequently encountered as residents cared for patients. Yet, faculty preceptors infrequently explicitly identified or taught these issues during their interactions with residents. Ethics education is important and residents may regard teaching about the ethics-related issues they actually encounter to be highly relevant. A better understanding of the barriers to teaching is needed in order to promote education about everyday ethics in the out-patient setting. © Blackwell Publishing Ltd 2011.

Everyday ethics in internal medicine resident clinic: an opportunity to teach

PubMed Central

Carrese, Joseph A; McDonald, Erin L; Moon, Margaret; Taylor, Holly A; Khaira, Kiran; Beach, Mary Catherine; Hughes, Mark T

2011-01-01

OBJECTIVES Being a good doctor requires competency in ethics. Accordingly, ethics education during residency training is important. We studied the everyday ethics-related issues (i.e. ordinary ethics issues commonly faced) that internal medical residents encounter in their out-patient clinic and determined whether teaching about these issues occurred during faculty preceptor–resident interactions. METHODS This study involved a multi-method qualitative research design combining observation of preceptor-resident discussions with preceptor interviews. The study was conducted in two different internal medicine training programme clinics over a 2-week period in June 2007. Fifty-three residents and 19 preceptors were observed, and 10 preceptors were interviewed. Transcripts of observer field notes and faculty interviews were carefully analysed. The analysis identified several themes of everyday ethics issues and determined whether preceptors identified and taught about these issues. RESULTS Everyday ethics content was considered present in 109 (81%) of the 135 observed case presentations. Three major thematic domains and associated sub-themes related to everyday ethics issues were identified, concerning: (i) the Doctor–Patient Interaction (relationships; communication; shared decision making); (ii) the Resident as Learner (developmental issues; challenges and conflicts associated with training; relationships with colleagues and mentors; interactions with the preceptor), and; (iii) the Doctor–System Interaction (financial issues; doctor–system issues; external influences; doctor frustration related to system issues). Everyday ethics issues were explicitly identified by preceptors (without teaching) in 18 of 109 cases (17%); explicit identification and teaching occurred in only 13 cases (12%). CONCLUSIONS In this study a variety of everyday ethics issues were frequently encountered as residents cared for patients. Yet, faculty preceptors infrequently explicitly identified or taught these issues during their interactions with residents. Ethics education is important and residents may regard teaching about the ethics-related issues they actually encounter to be highly relevant. A better understanding of the barriers to teaching is needed in order to promote education about everyday ethics in the out-patient setting. PMID:21649704

Effects of selective attention on continuous opinions and discrete decisions

NASA Astrophysics Data System (ADS)

Si, Xia-Meng; Liu, Yun; Xiong, Fei; Zhang, Yan-Chao; Ding, Fei; Cheng, Hui

2010-09-01

Selective attention describes that individuals have a preference on information according to their involving motivation. Based on achievements of social psychology, we propose an opinion interacting model to improve the modeling of individuals’ interacting behaviors. There are two parameters governing the probability of agents interacting with opponents, i.e. individual relevance and time-openness. It is found that, large individual relevance and large time-openness advance the appearance of large clusters, but large individual relevance and small time-openness favor the lessening of extremism. We also put this new model into application to work out some factor leading to a successful product. Numerical simulations show that selective attention, especially individual relevance, cannot be ignored by launcher firms and information spreaders so as to attain the most successful promotion.

Reporting observational studies of the use of information technology in the clinical consultation. A position statement from the IMIA Primary Health Care Informatics Working Group (IMIA PCI WG).

PubMed

de Lusignan, S; Pearce, C; Kumarapeli, P; Stavropoulou, C; Kushniruk, A; Sheikh, A; Shachak, A; Mendis, K

2011-01-01

To develop a classification system to improve the reporting of observational studies of the use of information technology (IT) in clinical consultations. Literature review, workshops, and development of a position statement. We grouped the important aspects for consistent reporting into a "faceted classification"; the components relevant to a particular study to be used independently. The eight facets of our classification are: (1) Theoretical and methodological approach: e.g. dramaturgical, cognitive; (2) DATA COLLECTION: Type and method of observation; (3) Room layout and environment: How this affects interaction between clinician, patient and computer. (4) Initiation and Interaction: Who starts the consultation, and how the participants interact; (5) Information and knowledge utilisation: What sources of information or decision support are used or provided; (6) Timing and type of consultation variables: Standard descriptors that can be used to allow comparison of duration and description of continuous activities (e.g. speech, eye contact) and episodic ones, such as prescribing; (7) Post-consultation impact measures: Satisfaction surveys and health economic assessment based on the perceived quality of the clinician-patient interaction; and (8) Data capture, storage, and export formats: How to archive and curate data to facilitate further analysis. Adoption of this classification should make it easier to interpret research findings and facilitate the synthesis of evidence across studies. Those engaged in IT-consultation research shouldconsider adopting this reporting guide.

Modulation of kinase-inhibitor interactions by auxiliary protein binding: Crystallography studies on Aurora A interactions with VX-680 and with TPX2

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

Zhao, Baoguang; Smallwood, Angela; Yang, Jingsong

2008-10-24

VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 {angstrom} resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a {pi}-{pi} interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggestmore » that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.« less

Primary Characterization of Small RNAs in Symbiotic Nitrogen-Fixing Bacteria.

PubMed

Robledo, Marta; García-Tomsig, Natalia I; Jiménez-Zurdo, José I

2018-01-01

High-throughput transcriptome profiling (RNAseq) has uncovered large and heterogeneous populations of small noncoding RNA species (sRNAs) with potential regulatory roles in bacteria. A large fraction of sRNAs are differentially regulated and rely on protein-assisted antisense interactions to trans-encoded target mRNAs to fine-tune posttranscriptional reprogramming of gene expression in response to external cues. However, annotation and function of sRNAs are still largely overlooked in nonmodel bacteria with complex lifestyles. Here, we describe experimental protocols successfully applied for the accurate annotation, expression profiling and target mRNA identification of trans-acting sRNAs in the nitrogen-fixing α-rhizobium Sinorhizobium meliloti. The protocols presented here can be similarly applied for the characterization of trans-sRNAs in genetically tractable α-proteobacteria of agronomical or clinical relevance interacting with eukaryotic hosts.

Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy.

PubMed

Goldstein, Lee E; McKee, Ann C; Stanton, Patric K

2014-01-01

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.

Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy

PubMed Central

2014-01-01

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath. PMID:25478023

13A. Integrative Cancer Care: The Life Over Cancer Model

PubMed Central

Block, Keith; Block, Penny; Shoham, Jacob

2013-01-01

Focus Areas: Integrative Algorithms of Care Integrative cancer treatment fully blends conventional cancer treatment with integrative therapies such as diet, supplements, exercise and biobehavioral approaches. The Life Over Cancer model comprises three spheres of intervention: improving lifestyle, improving biochemical environment (terrain), and improving tolerance of conventional treatment. These levels are applied within the context of a life-affirming approach to cancer patients and treatment. Clinical staff involved include MDs, psychosocial, physical therapy, and dietetic professionals, all located in a single private clinic, the Block Center for Integrative Cancer Treatment. This session will describe the rationale and operation of the clinical model. An outpatient chemotherapy unit is incorporated in the clinic. Chronomodulated chemotherapy is used for selected chemotherapy drugs. Physical care includes massage, exercise and other therapies as directed by the center's physical therapy staff. Notably, cancer patients who are physically active have lower mortality and recurrence risks. Behavioral approaches are being shown increasingly to affect physiological parameters and expression of genes potentially related to cancer. Thus, biobehavioral approaches such as relaxed abdominal breathing and comfort space imagery are taught to patients by a staff including a clinical psychologist and other practitioners. Nutrition is also emerging as a relevant area of intervention in cancer, with recent guidelines from the American Cancer Society. A team of registered dietitians counsels patients individually and conducts cooking classes. Finally, the Life Over Cancer model includes analysis of multiple biological parameters relevant to cancer and general health, with standard laboratory tests. Inflammation, glycemic variables, immune functioning and other variables are regularly monitored. Dietary changes and where necessary supplements are suggested when laboratory results are abnormal. Interaction of supplements with cancer treatment drugs is monitored. The session will highlight the roles played by both conventional and integrative therapies in the treatment of cancer patients.

Nutritional Management of Metabolic Endotoxemia: A Clinical Review.

PubMed

Brown, Benjamin I

2017-07-01

Context • Diet-induced, metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic diseases, including cardiometabolic, autoimmune, psychiatric, and neurodegenerative illnesses. Emerging human clinical studies have demonstrated that diet and dietary components are potent modifiers of circulating endotoxins and can be used to reduce plasma levels significantly and improve metabolic health. Objective • The aim of the current study was to explore briefly the concept of metabolic endotoxemia and its relationship to disease development, to examine the influence of diet and dietary components on circulating endotoxins, and, finally, discuss the clinical relevance of nutritional interventions for management of metabolic endotoxemia. Design • The researcher performed a literature review of dietary and nutritional interactions with metabolic endotoxemia with a focus on studies relevant to clinical practice. Setting • The study took place at the UK College of Nutrition and Health (London, England). Results • Improving dietary quality, optimizing the intake of phytonutrient-rich foods, improving micronutrient status, consuming fermented foods, manipulating the gut microflora with prebiotics and probiotics, and using specific nutritional supplements, such as glutamine, lactoferrin, resveratrol, and berberine, have been shown to be effective in targeting metabolic endotoxemia. Conclusions • Diet, dietary components, and nutritional supplements, including prebiotics and probiotics, have demonstrated the ability to provide clinically important reductions in circulating endotoxins and improve related sequels, such as inflammation and other negative health markers. The development of personalized nutritional interventions for the management of metabolic endotoxemia is a promising area for future research due to the potential of such interventions to improve multiple aspects of human health and mitigate a wide range of chronic diseases.

Implementing a sustainable clinical supervision model for Isles nurses in Orkney.

PubMed

Hall, Ian

2018-03-02

The Isles Network of Care (INOC) community nurses work at the extreme of the remote and rural continuum, working mostly as lone practitioners. Following the development of sustainable clinical supervision model for Isles nurses in Orkney, clinical supervision was found to improve both peer support and governance for this group of isolated staff. A literature overview identified the transition of clinical supervision in general nursing over 24 years from 'carrot' to 'stick'. The study included a questionnaire survey that was sent to the 2017 Queen's Nursing Institute Scotland cohort to elicit information about the nurses' experience of clinical supervision. The survey found that 55% provide supervision and 40% receive it. Health board encouragement of its use was found to be disappointingly low at 40%. The INOC nurses were surveyed about the new peer-support (restorative) model, which relies on video-conference contact to allow face to face interaction between isolated isles nurses. Feedback prompted a review of clinical supervision pairings, and the frequency and methods of meeting. The need for supervisor training led to agreement with the Remote and Rural Health Education Alliance to provide relevant support. The perceived benefits of supervision included increased support and reflection, and improved relationships with isolated colleagues.

Integrated inference and evaluation of host–fungi interaction networks

PubMed Central

Remmele, Christian W.; Luther, Christian H.; Balkenhol, Johannes; Dandekar, Thomas; Müller, Tobias; Dittrich, Marcus T.

2015-01-01

Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host–pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host–fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen–host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi–human and fungi–mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host–fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host–fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host–fungi transcriptome and proteome data. PMID:26300851

Identifying Opportunities for Vertical Integration of Biochemistry and Clinical Medicine.

PubMed

Wendelberger, Karen J.; Burke, Rebecca; Haas, Arthur L.; Harenwattananon, Marisa; Simpson, Deborah

1998-01-01

Objectives: Retention of basic science knowledge, as judged by National Board of Medical Examiners' (NBME) data, suffers due to lack of apparent relevance and isolation of instruction from clinical application, especially in biochemistry. However, the literature reveals no systematic process for identifying key biochemical concepts and associated clinical conditions. This study systematically identified difficult biochemical concepts and their common clinical conditions as a critical step towards enhancing relevance and retention of biochemistry.Methods: A multi-step/ multiple stakeholder process was used to: (1) identify important biochemistry concepts; (2) determine students' perceptions of concept difficulty; (3) assess biochemistry faculty, student, and clinical teaching scholars' perceived relevance of identified concepts; and (4) identify associated common clinical conditions for relevant and difficult concepts. Surveys and a modified Delphi process were used to gather data, subsequently analyzed using SPSS for Windows.Results: Sixteen key biochemical concepts were identified. Second year medical students rated 14/16 concepts as extremely difficult while fourth year students rated nine concepts as moderately to extremely difficult. On average, each teaching scholar generated common clinical conditions for 6.2 of the 16 concepts, yielding a set of seven critical concepts and associated clinical conditions.Conclusions: Key stakeholders in the instructional process struggle to identify biochemistry concepts that are critical, difficult to learn and associated with common clinical conditions. However, through a systematic process beginning with identification of concepts and associated clinical conditions, relevance of basic science instruction can be enhanced.

Make induction day more effective - add a few problems.

PubMed

Mitchell, H E; Laidlaw, J M

1999-06-01

Induction courses are important to introduce Pre-Registration House Officers (PRHOs) to their new place of work. Traditionally, such programmes employ lectures, small group discussion and demonstrations. They let PRHOs meet members of various hospital disciplines and services. Since 1991, an interactive induction programme has been held each August for new PRHOs in the Eastern Region of Scotland taking up posts in Dundee Teaching Hospitals NHS Trust. Feedback from participants allows the course to be refined each year. In 1995, three paper-based patient management problems (PMPs) were included in the induction programme. Response was favourable. Most of the participants (82%) suggested the PMPs should be used again, but that more time should be allocated to enable them to tackle the problems. By August 1996, we aimed to provide a relevant and interactive programme that encouraged PRHOs to make immediate use of hospital resources. Two PMPs, in print format described likely case histories, with tasks that mirrored the junior doctors' forthcoming responsibilities. Healthcare team members and laboratory staff provided support as did study boards displaying written sheets of relevant clinical information. In the subsequent evaluation, the PMP component was rated highly by participants. They effectively triggered PRHOs to interact with hospital staff. We conclude that PMPs provide a valuable learning experience for junior doctors and are a useful addition to an induction day programme. We plan to refine and increase the use of PMPs in undergraduate and postgraduate settings.

The capacity of people with a 'mental disability' to make a health care decision.

PubMed

Wong, J G; Clare, C H; Holland, A J; Watson, P C; Gunn, M

2000-03-01

Based on the developing clinical and legal literature, and using the framework adopted in draft legislation, capacity to make a valid decision about a clinically required blood test was investigated in three groups of people with a 'mental disability' (i.e. mental illness (chronic schizophrenia), 'learning disability' ('mental retardation', or intellectual or developmental disability), or, dementia) and a fourth, comparison group. The three 'mental disability' groups (N = 20 in the 'learning disability' group, N = 21 in each of the other two groups) were recruited through the relevant local clinical services; and through a phlebotomy clinic for the 'general population' comparison group (N = 20). The decision-making task was progressively simplified by presenting the relevant information as separate elements and modifying the assessment of capacity so that responding became gradually less dependent on expressive verbal ability. Compared with the 'general population' group, capacity to make the particular decision was significantly more impaired in the 'learning disability' and 'dementia' groups. Importantly, however, it was not more impaired among the 'mental illness' group. All the groups benefited as the decision-making task was simplified, but at different stages. In each of the 'mental disability' groups, one participant benefited only when responding did not require any expensive verbal ability. Consistent with current views, capacity reflected an interaction between the decision-maker and the demands of the decision-making task. The findings have implications for the way in which decisions about health care interventions are sought from people with a 'mental disability'. The methodology may be extended to assess capacity to make other legally-significant decisions.

Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons

PubMed Central

Beske, Phillip H.; Bradford, Aaron B.; Grynovicki, Justin O.; Glotfelty, Elliot J.; Hoffman, Katie M.; Hubbard, Kyle S.; Tuznik, Kaylie M.; McNutt, Patrick M.

2016-01-01

Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A–G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays. PMID:26615023

Using novel descriptor accounting for ligand-receptor interactions to define and visually explore biologically relevant chemical space.

PubMed

Rabal, Obdulia; Oyarzabal, Julen

2012-05-25

The definition and pragmatic implementation of biologically relevant chemical space is critical in addressing navigation strategies in the overlapping regions where chemistry and therapeutically relevant targets reside and, therefore, also key to performing an efficient drug discovery project. Here, we describe the development and implementation of a simple and robust method for representing biologically relevant chemical space as a general reference according to current knowledge, independently of any reference space, and analyzing chemical structures accordingly. Underlying our method is the generation of a novel descriptor (LiRIf) that converts structural information into a one-dimensional string accounting for the plausible ligand-receptor interactions as well as for topological information. Capitalizing on ligand-receptor interactions as a descriptor enables the clustering, profiling, and comparison of libraries of compounds from a chemical biology and medicinal chemistry perspective. In addition, as a case study, R-groups analysis is performed to identify the most populated ligand-receptor interactions according to different target families (GPCR, kinases, etc.), as well as to evaluate the coverage of biologically relevant chemical space by structures annotated in different databases (ChEMBL, Glida, etc.).

Retention of knowledge and perceived relevance of basic sciences in an integrated case-based learning (CBL) curriculum

PubMed Central

2013-01-01

Background Knowledge and understanding of basic biomedical sciences remain essential to medical practice, particularly when faced with the continual advancement of diagnostic and therapeutic modalities. Evidence suggests, however, that retention tends to atrophy across the span of an average medical course and into the early postgraduate years, as preoccupation with clinical medicine predominates. We postulated that perceived relevance demonstrated through applicability to clinical situations may assist in retention of basic science knowledge. Methods To test this hypothesis in our own medical student cohort, we administered a paper-based 50 MCQ assessment to a sample of students from Years 2 through 5. Covariates pertaining to demographics, prior educational experience, and the perceived clinical relevance of each question were also collected. Results A total of 232 students (Years 2–5, response rate 50%) undertook the assessment task. This sample had comparable demographic and performance characteristics to the whole medical school cohort. In general, discipline-specific and overall scores were better for students in the latter years of the course compared to those in Year 2; male students and domestic students tended to perform better than their respective counterparts in certain disciplines. In the clinical years, perceived clinical relevance was significantly and positively correlated with item performance. Conclusions This study suggests that perceived clinical relevance is a contributing factor to the retention of basic science knowledge and behoves curriculum planners to make clinical relevance a more explicit component of applied science teaching throughout the medical course. PMID:24099045

Does the choice of display system influence perception and visibility of clinically relevant features in digital pathology images?

NASA Astrophysics Data System (ADS)

Kimpe, Tom; Rostang, Johan; Avanaki, Ali; Espig, Kathryn; Xthona, Albert; Cocuranu, Ioan; Parwani, Anil V.; Pantanowitz, Liron

2014-03-01

Digital pathology systems typically consist of a slide scanner, processing software, visualization software, and finally a workstation with display for visualization of the digital slide images. This paper studies whether digital pathology images can look different when presenting them on different display systems, and whether these visual differences can result in different perceived contrast of clinically relevant features. By analyzing a set of four digital pathology images of different subspecialties on three different display systems, it was concluded that pathology images look different when visualized on different display systems. The importance of these visual differences is elucidated when they are located in areas of the digital slide that contain clinically relevant features. Based on a calculation of dE2000 differences between background and clinically relevant features, it was clear that perceived contrast of clinically relevant features is influenced by the choice of display system. Furthermore, it seems that the specific calibration target chosen for the display system has an important effect on the perceived contrast of clinically relevant features. Preliminary results suggest that calibrating to DICOM GSDF calibration performed slightly worse than sRGB, while a new experimental calibration target CSDF performed better than both DICOM GSDF and sRGB. This result is promising as it suggests that further research work could lead to better definition of an optimized calibration target for digital pathology images resulting in a positive effect on clinical performance.

Quantifying peer interactions for research and clinical use: the Manchester Inventory for Playground Observation.

PubMed

Gibson, Jenny; Hussain, Jamilla; Holsgrove, Samina; Adams, Catherine; Green, Jonathan

2011-01-01

Direct observation of peer relating is potentially a sensitive and ecologically valid measure of child social functioning, but there has been a lack of standardised methods. The Manchester Inventory for Playground Observation (MIPO) was developed as a practical yet rigorous assessment of this kind for 5-11 year olds. We report on the initial reliability and validity of the MIPO and its ability to distinguish social impairments within different psychopathologies. We observed 144 clinically referred children aged 5;00-11;11 (mean 8.8) years with Externalising (n = 44), Internalising (n = 19), Autism Spectrum Disorders (n = 39) or Specific Language Impairment (n = 42), and 44 class-controls, in naturalistic playground interaction. Observers, blind to clinical diagnosis, completed the MIPO and the teacher checklist from the Social Skills Rating System (SSRS). MIPO items showed high internal consistency (alpha = .924; all 'alpha if item deleted' values>.91), inter-observer reliability (mean κ(w) = .77) and test-retest stability (over 2 weeks; mean κ(w) = .58). MIPO totals showed convergence with SSRS (n = 68, r(s) = .78, p<.01) and excellent discrimination between case and control (sensitivity = 0.75 and specificity = 0.88, AUC = .897). Externalising, Autistic Spectrum and Language Impaired groups showed distinct profiles of MIPO impairment consistent with theory:Internalising disorders less so. 65.3% of clinical cases were classified accurately for primary diagnosis. The MIPO shows reliability and validity as a measure of children's social functioning relevant in developmental research and as a clinical tool to aid differential diagnosis and intervention planning. Copyright © 2011 Elsevier Ltd. All rights reserved.

Detecting clinically relevant new information in clinical notes across specialties and settings.

PubMed

Zhang, Rui; Pakhomov, Serguei V S; Arsoniadis, Elliot G; Lee, Janet T; Wang, Yan; Melton, Genevieve B

2017-07-05

Automated methods for identifying clinically relevant new versus redundant information in electronic health record (EHR) clinical notes is useful for clinicians and researchers involved in patient care and clinical research, respectively. We evaluated methods to automatically identify clinically relevant new information in clinical notes, and compared the quantity of redundant information across specialties and clinical settings. Statistical language models augmented with semantic similarity measures were evaluated as a means to detect and quantify clinically relevant new and redundant information over longitudinal clinical notes for a given patient. A corpus of 591 progress notes over 40 inpatient admissions was annotated for new information longitudinally by physicians to generate a reference standard. Note redundancy between various specialties was evaluated on 71,021 outpatient notes and 64,695 inpatient notes from 500 solid organ transplant patients (April 2015 through August 2015). Our best method achieved at best performance of 0.87 recall, 0.62 precision, and 0.72 F-measure. Addition of semantic similarity metrics compared to baseline improved recall but otherwise resulted in similar performance. While outpatient and inpatient notes had relatively similar levels of high redundancy (61% and 68%, respectively), redundancy differed by author specialty with mean redundancy of 75%, 66%, 57%, and 55% observed in pediatric, internal medicine, psychiatry and surgical notes, respectively. Automated techniques with statistical language models for detecting redundant versus clinically relevant new information in clinical notes do not improve with the addition of semantic similarity measures. While levels of redundancy seem relatively similar in the inpatient and ambulatory settings in the Fairview Health Services, clinical note redundancy appears to vary significantly with different medical specialties.

Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment.

PubMed

Venkatakrishnan, K; Obach, R S; Rostami-Hodjegan, A

2007-01-01

Among drugs that cause pharmacokinetic drug-drug interactions, mechanism-based inactivators of cytochrome P450 represent several of those agents that cause interactions of the greatest magnitude. In vitro inactivation kinetic data can be used to predict the potential for new drugs to cause drug interactions in the clinic. However, several factors exist, each with its own uncertainty, that must be taken into account in order to predict the magnitude of interactions reliably. These include aspects of in vitro experimental design, an understanding of relevant in vivo concentrations of the inactivator, and the extent to which the inactivated enzyme is involved in the clearance of the affected drug. Additionally, the rate of enzyme degradation in vivo is also an important factor that needs to be considered in the prediction of the drug interaction magnitudes. To address mechanism-based inactivation for new drugs, various in vitro experimental approaches have been employed. The selection of approaches for in vitro kinetic characterization of inactivation as well as in vitro-in vivo extrapolation should be guided by the purpose of the exercise and the stage of drug discovery and development, with an increase in the level of sophistication throughout the research and development process.

[Modeling the academic performance of medical students in basic sciences and pre-clinical courses: a longitudinal study].

PubMed

Zúñiga, Denisse; Mena, Beltrán; Oliva, Rose; Pedrals, Nuria; Padilla, Oslando; Bitran, Marcela

2009-10-01

The study of predictors of academic performance is relevant for medical education. Most studies of academic performance use global ratings as outcome measure, and do not evaluate the influence of the assessment methods. To model by multivariate analysis, the academic performance of medical considering, besides academic and demographic variables, the methods used to assess students' learning and their preferred modes of information processing. Two hundred seventy two students admitted to the medical school of the Pontificia Universidad Católica de Chile from 2000 to 2003. Six groups of variables were studied to model the students' performance in five basic science courses (Anatomy, Biology, Calculus, Chemistry and Physics) and two pre-clinical courses (Integrated Medical Clinic I and IT). The assessment methods examined were multiple choice question tests, Objective Structured Clinical Examination and tutor appraisal. The results of the university admission tests (high school grades, mathematics and biology tests), the assessment methods used, the curricular year and previous application to medical school, were predictors of academic performance. The information processing modes influenced academic performance, but only in interaction with other variables. Perception (abstract or concrete) interacted with the assessment methods, and information use (active or reflexive), with sex. The correlation between the real and predicted grades was 0.7. In addition to the academic results obtained prior to university entrance, the methods of assessment used in the university and the information processing modes influence the academic performance of medical students in basic and preclinical courses.

The Effects of Clinically Relevant Multiple-Choice Items on the Statistical Discrimination of Physician Clinical Competence.

ERIC Educational Resources Information Center

Downing, Steven M.; Maatsch, Jack L.

To test the effect of clinically relevant multiple-choice item content on the validity of statistical discriminations of physicians' clinical competence, data were collected from a field test of the Emergency Medicine Examination, test items for the certification of specialists in emergency medicine. Two 91-item multiple-choice subscales were…

Prescription Writing in Small Groups as a Clinical Pharmacology Educational Intervention: Perceptions of Preclerkship Medical Students.

PubMed

James, Henry; Tayem, Yasin I Y; Al Khaja, K A J; Veeramuthu, Sindhan; Sequeira, Reginald P

2016-08-01

Medical students do not perform well in writing prescriptions, and the 3 variables-learner, teacher, and instructional method-are held responsible to various degrees. The objective of this clinical pharmacology educational intervention was to improve medical students' perceptions, motivation, and participation in prescription-writing sessions. The study participants were second-year medical students of the College of Medicine and Medical Sciences of the Arabian Gulf University, Bahrain. Two prescription-writing sessions were conducted using clinical case scenarios based on problems the students had studied as part of the problem-based learning curriculum. At the end of the respiratory system subunit, the training was conducted in small groups, each facilitated by a tutor. At the end of the cardiovascular system subunit, the training was conducted in a traditional large-group classroom setting. Data were collected with the help of a questionnaire at the end of each session and a focus group discussion. A majority of the students (95.3% ± 2.4%) perceived the small-group method better for teaching and learning of all aspects of prescription writing: analyzing the clinical case scenario, applying clinical pharmacology knowledge for therapeutic reasoning, using a formulary for searching relevant prescribing information, and in writing a complete prescription. Students also endorsed the small-group method for better interaction among themselves and with the tutor and for the ease of asking questions and clarifying doubts. In view of the principles of adult learning, where motivation and interaction are important, teaching and learning prescription writing in small groups deserve a serious consideration in medical curricula. © 2015, The American College of Clinical Pharmacology.

The association of admission hyperglycaemia and adverse clinical outcome in medical emergencies: the multinational, prospective, observational TRIAGE study.

PubMed

Kutz, A; Struja, T; Hausfater, P; Amin, D; Amin, A; Haubitz, S; Bernard, M; Huber, A; Mueller, B; Schuetz, P

2017-07-01

The clinical relevance of hyperglycaemia in an emergency department population remains incompletely understood. We investigated the association between admission blood glucose levels and adverse clinical outcomes in a large emergency department cohort. We prospectively enrolled 7132 adult medical patients seeking emergency department care in three tertiary care hospitals in Switzerland, France and the USA. We used adjusted multivariable logistic regression models to examine the association between admission blood glucose levels and 30-day mortality, as well as adverse clinical course stratified by pre-existing diabetes and principal medical diagnoses. In 6044 people without diabetes (84.7%), severe hyperglycaemia, defined as a glucose level of > 11.1 mmol/l (200 mg/dl), was associated with a doubling in the risk of 30-day mortality [adjusted odds ratio (OR) 1.9; 95% confidence interval (95% CI), 1.1 to 3.3; P = 0.018] and a three-fold increase in the risk of intensive care unit admission (adjusted OR 3.0; 95% CI, 1.9 to 4.9; P < 0.001). These associations were similar among different diagnoses. In the population with diabetes (n = 1088), no association with 30-day mortality was found (adjusted OR 1.0; 95% CI, 0.6 to 1.8; P for interaction = 0.001), whereas the association with intensive care unit admission was weaker (adjusted OR 2.4; 95% CI, 1.5 to 4.1; P for interaction = 0.011). Overall 30-day mortality was higher in those with diabetes than in those without (6.1 vs. 4.4%, P = 0.015). In this large medical emergency department patient cohort, admission hyperglycaemia was strongly associated with adverse clinical course in people without diabetes. (Clinical Trial Registry No: NCT01768494). © 2017 Diabetes UK.

Privacy protection for clinical and genomic data. The use of privacy-enhancing techniques in medicine.

PubMed

Claerhout, B; DeMoor, G J E

2005-03-01

Privacy includes the right of individuals and organisations to determine for themselves when, how and to what extent information about them is communicated to others. The growing need of managing large amounts of both clinical and genetic data raises important legal and ethical challenges. This paper introduces some of the privacy-protection problems related to classical and genomic medicine, and highlights the relevance of trusted third parties and of privacy-enhancing techniques (PETs) in the context of data collection, e.g., for research. Practical approaches based on two pseudonymisation models, for both batch data collection and interactive data storage, are presented. The actual application of the described techniques today proves the possible benefits for medicine that innovative privacy-enhancing techniques can provide. Technical PET solutions can unlock valuable data sources, otherwise not available.

Measuring interactivity on tobacco control websites.

PubMed

Freeman, Becky; Chapman, Simon

2012-08-01

With the increased reach of Web 2.0, Internet users expect webpages to be interactive. No studies have been conducted to assess whether tobacco control-relevant sites have implemented these features. The authors conducted an analysis of an international sample of tobacco control-relevant websites to determine their level of interactivity. The sample included 68 unique websites selected from Google searches in 5 countries, on each country's Google site, using the term smoking. The 68 sites were analyzed for 10 categories of interactive tools. The most common type of interactive content found on 46 (68%) of sites was for multimedia featuring content that was not primarily text based, such as photo galleries, videos, or podcasts. Only 11 (16%) websites-outside of media sites-allowed people to interact and engage with the site owners and other users by allowing posting comments on content and/or hosting forums/discussions. Linkages to social networking sites were low: 17 pages (25%) linked to Twitter, 15 (22%) to Facebook, and 11 (16%) to YouTube. Interactivity and connectedness to online social media appears to still be in its infancy among tobacco control-relevant sites.

Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study

PubMed Central

2012-01-01

Background The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. Results Our findings demonstrate that a miRNA’s functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA-regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. Conclusions We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment. PMID:22929553

Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide.

PubMed

Custodio, Joseph M; Chuck, Susan K; Chu, Hoa; Cao, Huyen; Ma, Grace; Flaherty, John; Ling, John; Kearney, Brian P

2017-10-01

The drug-drug interaction (DDI) potential between the fixed-dose combinations of ledipasvir/sofosbuvir 90/400 mg for hepatitis C virus and emtricitabine/rilpivirine/tenofovir alafenamide (TAF) 200/25/25 mg for HIV was evaluated in a randomized, open-label, single-center, multiple-dose, 3-way, 6-sequence, crossover Phase 1 study in 42 healthy subjects. Emtricitabine/rilpivirine/TAF had no relevant effect on the pharmacokinetic parameters of maximum concentration [C max ] and area under the concentration versus time curve over the dosing interval [AUC tau ] for ledipasvir, sofosbuvir, and the metabolites GS-566500 and GS-331007. Ledipasvir/sofosbuvir had no effect on the C max and AUC tau for rilpivirine and emtricitabine. The C max and AUC tau of tenofovir, the major metabolite of TAF, were increased by 62% and 75%, respectively. However, the resulting absolute tenofovir exposures were markedly lower than the historical tenofovir exposures following tenofovir disoproxil fumarate (TDF) and, as such, were not considered to be clinically relevant. In contrast, additional adverse effect monitoring is recommended upon coadministration of ledipasvir and TDF due to elevated tenofovir exposures resulting from the DDI. This difference is explained by the fact that TAF 25 mg results in markedly lower (~90%) plasma tenofovir exposure compared to TDF 300 mg. Ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF were generally well tolerated when administered alone or in combination. HIV/hepatitis C virus-coinfected patients can coadminister ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF without dosage adjustments. © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

What motivates family physicians to participate in training programs in shared decision making?

PubMed

Allaire, Anne-Sophie; Labrecque, Michel; Giguere, Anik; Gagnon, Marie-Pierre; Légaré, France

2012-01-01

Little is known about the factors that influence family physician (FP) participation in continuing professional development (CPD) programs in shared decision making (SDM). We sought to identify the factors that motivate FPs to participate in DECISION+, a CPD program in SDM. In 2007-2008, we collected data from 39 FPs who participated in a pilot randomized trial of DECISION+. In 2010, we collected data again from 11 of those participants and from 12 new subjects. Based on the theory of planned behavior, our questionnaire assessed FPs' intentions to participate in a CPD program in SDM and evaluated FPs' attitudes, subjective norms and perceived behavioral control. We also conducted 4 focus groups to explore FPs' salient beliefs. In 2010, FPs' mean intention to participate in a CPD program in SDM was relatively strong (2.6 ± 0.5 on a scale from -3 = "strongly disagree" to +3 = "strongly agree"). Affective attitude was the only factor significantly associated with intention (r = .51, p = .04). FPs identified the attractions of participating in a CPD program in SDM as (1) its interest, (2) the pleasure of learning, and (3) professional stimulation. Facilitators of their participation were (1) a relevant clinical topic, (2) an interactive program, (3) an accessible program, and (4) decision support tools. To attract FPs to a CPD program in SDM, CPD developers should make the program interesting, enjoyable, and professionally stimulating. They should choose a clinically relevant topic, ensure that the program is interactive and accessible, and include decision support tools. Copyright © 2012 The Alliance for Continuing Education in the Health Professions, the Society for Academic Continuing Medical Education, and the Council on CME, Association for Hospital Medical Education.

Back to Anatomy: Improving Landmarking Accuracy of Clinical Procedures Using a Novel Approach to Procedural Teaching.

PubMed

Zeller, Michelle; Cristancho, Sayra; Mangel, Joy; Goldszmidt, Mark

2015-06-01

Many believe that knowledge of anatomy is essential for performing clinical procedures; however, unlike their surgical counterparts, internal medicine (IM) programs rarely incorporate anatomy review into procedural teaching. This study tested the hypothesis that an educational intervention focused on teaching relevant surface and underlying anatomy would result in improved bone marrow procedure landmarking accuracy. This was a preintervention-postintervention prospective study on landmarking accuracy of consenting IM residents attending their mandatory academic half-day. The intervention included an interactive video and visualization exercise; the video was developed specifically to teach the relevant underlying anatomy and includes views of live volunteers, cadavers, and skeletons. Thirty-one IM residents participated. At pretest, 48% (15/31) of residents landmarked accurately. Inaccuracy of pretest landmarking varied widely (n = 16, mean 20.06 mm; standard deviation 30.03 mm). At posttest, 74% (23/31) of residents accurately performed the procedure. McNemar test revealed a nonsignificant trend toward increased performance at posttest (P = 0.076; unadjusted odds for discordant pairs 3; 95% confidence interval 0.97-9.3). The Wilcoxon signed rank test demonstrated a significant difference between pre- and posttest accuracy in the 16 residents who were inaccurate at pretest (P = 0.004). No association was detected between participant baseline characteristics and pretest accuracy. This study demonstrates that residents who were initially inaccurate were able to significantly improve their landmarking skills by interacting with an educational tool emphasizing the relation between the surface and underlying anatomy. Our results support the use of basic anatomy in teaching bone marrow procedures. Results also support the proper use of video as an effective means for incorporating anatomy teaching around procedural skills.

[The diagnostic process in spina bifida: parents perception and viewpoint of clinical specialists].

PubMed

Herb, G; Streeck, S

1995-01-01

This is a study of the subjective experience of communicative understanding between parents of spina bifida children and medical personnel. Research methods include content analysis of data from semi-structured interviews, a questionnaire to explore the quality of life as well as conversation analytic reconstructions of the "real" communication processes during outpatient clinic which were tape-recorded. Results of the interviews with parents and personnel demonstrate the great relevance of the quality of the relationship in the providing of clinical care; equally important is that the relationship between parents and clinic staff is shaped in a reciprocal fashion. Discrepancies in the perceptions of parents and personnel indicate individual reality constructions. It is desirable that parents and personnel construct a shared reality during their interaction. With respect to this end, the emotional resources of personnel should be regarded as competences and drawn upon more systematically. The parents' role as "experts" should be validated and their active participation in the construction of the communicative situation - which is normally determined by the institution - should be encouraged.

Cognitive Analysis of Decision Support for Antibiotic Prescribing at the Point of Ordering in a Neonatal Intensive Care Unit

PubMed Central

Sheehan, Barbara; Kaufman, David; Stetson, Peter; Currie, Leanne M.

2009-01-01

Computerized decision support systems have been used to help ensure safe medication prescribing. However, the acceptance of these types of decision support has been reported to be low. It has been suggested that decreased acceptance may be due to lack of clinical relevance. Additionally, cognitive fit between the user interface and clinical task may impact the response of clinicians as they interact with the system. In order to better understand clinician responses to such decision support, we used cognitive task analysis methods to evaluate clinical alerts for antibiotic prescribing in a neonatal intensive care unit. Two methods were used: 1) a cognitive walkthrough; and 2) usability testing with a ‘think-aloud’ protocol. Data were analyzed for impact on cognitive effort according to categories of cognitive distance. We found that responses to alerts may be context specific and that lack of screen cues often increases cognitive effort required to use a system. PMID:20351922

Stabilization of p21 by mTORC1/4E-BP1 predicts clinical outcome of head and neck cancers

PubMed Central

Llanos, Susana; García-Pedrero, Juana M.; Morgado-Palacin, Lucia; Rodrigo, Juan P.; Serrano, Manuel

2016-01-01

The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC. PMID:26832959

Fluorescence fluctuation spectroscopy for clinical applications

NASA Astrophysics Data System (ADS)

Olson, Eben

Fluorescence correlation spectroscopy (FCS) and the related techniques of brightness analysis have become standard tools in biological and biophysical research. By analyzing the statistics of fluorescence emitted from a restricted volume, a number of parameters including concentrations, diffusion coefficients and chemical reaction rates can be determined. The single-molecule sensitivity, spectral selectivity, small sample volume and non-perturbative measurement mechanism of FCS make it an excellent technique for the study of molecular interactions. However, its adoption outside of the research laboratory has been limited. Potential reasons for this include the cost and complexity of the required apparatus. In this work, the application of fluorescence fluctuation analysis to several clinical problems is considered. Optical designs for FCS instruments which reduce the cost and increase alignment tolerance are presented. Brightness analysis of heterogenous systems, with application to the characterization of protein aggregates and multimer distributions, is considered. Methods for FCS-based assays of two clinically relevant proteins, von Willebrand factor and haptoglobin, are presented as well.

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students' learning.

PubMed

Edafe, Ovie; Brooks, William S; Laskar, Simone N; Benjamin, Miles W; Chan, Philip

2016-03-20

This study examines the perceived impact of a novel clinical teaching method based on FAIR principles (feedback, activity, individuality and relevance) on students' learning on clinical placement. This was a qualitative research study. Participants were third year and final year medical students attached to one UK vascular firm over a four-year period (N=108). Students were asked to write a reflective essay on how FAIRness approach differs from previous clinical placement, and its advantages and disadvantages. Essays were thematically analysed and globally rated (positive, negative or neutral) by two independent researchers. Over 90% of essays reported positive experiences of feedback, activity, individuality and relevance model. The model provided multifaceted feedback; active participation; longitudinal improvement; relevance to stage of learning and future goals; structured teaching; professional development; safe learning environment; consultant involvement in teaching. Students perceived preparation for tutorials to be time intensive for tutors/students; a lack of teaching on medical sciences and direct observation of performance; more than once weekly sessions would be beneficial; some issues with peer and public feedback, relevance to upcoming exam and large group sizes. Students described negative experiences of "standard" clinical teaching. Progressive teaching programmes based on the FAIRness principles, feedback, activity, individuality and relevance, could be used as a model to improve current undergraduate clinical teaching.

There's an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications.

PubMed

Wiechmann, Warren; Kwan, Daniel; Bokarius, Andrew; Toohey, Shannon L

2016-03-01

The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its "Medical" category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as "emergency medicine," "critical care," "orthopedics," and "procedures." Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non-English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store's "Medical" Category and 0.1% of the overall App Store. Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the Medical section of the App Store. Without a structured search-and-evaluation strategy, it may be difficult for the casual user to identify this potentially useful content. Given the increasing adoption of devices in healthcare, national EM associations should consider curating these resources for their members.

A randomized trial comparing INR monitoring devices in patients with anticoagulation self-management: evaluation of a novel error-grid approach.

PubMed

Hemkens, Lars G; Hilden, Kristian M; Hartschen, Stephan; Kaiser, Thomas; Didjurgeit, Ulrike; Hansen, Roland; Bender, Ralf; Sawicki, Peter T

2008-08-01

In addition to the metrological quality of international normalized ratio (INR) monitoring devices used in patients' self-management of long-term anticoagulation, the effectiveness of self-monitoring with such devices has to be evaluated under real-life conditions with a focus on clinical implications. An approach to evaluate the clinical significance of inaccuracies is the error-grid analysis as already established in self-monitoring of blood glucose. Two anticoagulation monitors were compared in a real-life setting and a novel error-grid instrument for oral anticoagulation has been evaluated. In a randomized crossover study 16 patients performed self-management of anticoagulation using the INRatio and the CoaguChek S system. Main outcome measures were clinically relevant INR differences according to established criteria and to the error-grid approach. A lower rate of clinically relevant disagreements according to Anderson's criteria was found with CoaguChek S than with INRatio without statistical significance (10.77% vs. 12.90%; P = 0.787). Using the error-grid we found principally consistent results: More measurement pairs with discrepancies of no or low clinical relevance were found with CoaguChek S, whereas with INRatio we found more differences with a moderate clinical relevance. A high rate of patients' satisfaction with both of the point of care devices was found with only marginal differences. A principal appropriateness of the investigated point-of-care devices to adequately monitor the INR is shown. The error-grid is useful for comparing monitoring methods with a focus on clinical relevance under real-life conditions beyond assessing the pure metrological quality, but we emphasize that additional trials using this instrument with larger patient populations are needed to detect differences in clinically relevant disagreements.

Sensitivity and Predictive Value of 15 PubMed Search Strategies to Answer Clinical Questions Rated Against Full Systematic Reviews

PubMed Central

Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-01-01

Background Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. Objective To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. Methods We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed’s Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. Results The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%–25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%–30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. Conclusions The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care. PMID:22693047

Sensitivity and predictive value of 15 PubMed search strategies to answer clinical questions rated against full systematic reviews.

PubMed

Agoritsas, Thomas; Merglen, Arnaud; Courvoisier, Delphine S; Combescure, Christophe; Garin, Nicolas; Perrier, Arnaud; Perneger, Thomas V

2012-06-12

Clinicians perform searches in PubMed daily, but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge. Little is known about the performance of search strategies when they are applied to answer specific clinical questions. To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions. We used Cochrane systematic reviews to identify relevant trials for 30 clinical questions. Search terms were extracted from the abstract using a predefined procedure based on the population, interventions, comparison, outcomes (PICO) framework and combined into queries. We tested 15 search strategies that varied in their query (PIC or PICO), use of PubMed's Clinical Queries therapeutic filters (broad or narrow), search limits, and PubMed links to related articles. We assessed sensitivity (recall) and positive predictive value (precision) of each strategy on the first 2 PubMed pages (40 articles) and on the complete search output. The performance of the search strategies varied widely according to the clinical question. Unfiltered searches and those using the broad filter of Clinical Queries produced large outputs and retrieved few relevant articles within the first 2 pages, resulting in a median sensitivity of only 10%-25%. In contrast, all searches using the narrow filter performed significantly better, with a median sensitivity of about 50% (all P < .001 compared with unfiltered queries) and positive predictive values of 20%-30% (P < .001 compared with unfiltered queries). This benefit was consistent for most clinical questions. Searches based on related articles retrieved about a third of the relevant studies. The Clinical Queries narrow filter, along with well-formulated queries based on the PICO framework, provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages. These results can help clinicians apply effective strategies to answer their questions at the point of care.

Optical diagnostics of osteoblast cells and osteogenic drug screening

NASA Astrophysics Data System (ADS)

Kolanti, Elayaraja; Veerla, Sarath C.; Khajuria, Deepak K.; Roy Mahapatra, D.

2016-02-01

Microfluidic device based diagnostics involving optical fibre path, in situ imaging and spectroscopy are gaining importance due to recent advances in diagnostics instrumentation and methods, besides other factors such as low amount of reagent required for analysis, short investigation times, and potential possibilities to replace animal model based study in near future. It is possible to grow and monitor tissues in vitro in microfluidic lab-on-chip. It may become a transformative way of studying how cells interact with drugs, pathogens and biomaterials in physiologically relevant microenvironments. To a large extent, progress in developing clinically viable solutions has been constrained because of (i) contradiction between in vitro and in vivo results and (ii) animal model based and clinical studies which is very expensive. Our study here aims to evaluate the usefulness of microfluidic device based 3D tissue growth and monitoring approach to better emulate physiologically and clinically relevant microenvironments in comparison to conventional in vitro 2D culture. Moreover, the microfluidic methodology permits precise high-throughput investigations through real-time imaging while using very small amounts of reagents and cells. In the present study, we report on the details of an osteoblast cell based 3D microfluidic platform which we employ for osteogenic drug screening. The drug formulation is functionalized with fluorescence and other biomarkers for imaging and spectroscopy, respectively. Optical fibre coupled paths are used to obtain insight regarding the role of stress/flow pressure fluctuation and nanoparticle-drug concentration on the osteoblast growth and osteogenic properties of bone.

New Clinically Relevant Findings about Violence by People with Schizophrenia.

PubMed

Hodgins, Sheilagh; Klein, Sanja

2017-02-01

To review findings with clinical relevance that add to knowledge about antisocial and aggressive behaviour among persons with schizophrenia. Nonsystematic literature review. Recent evidence shows that individuals who develop schizophrenia present cognitive deficits, psychotic-like experiences, and internalizing and externalizing problems from childhood onwards. Many of their relatives present not only schizophrenia-related disorders but also antisocial behaviour. While the increased risk of aggressive behaviour among persons with schizophrenia has been robustly established, recent findings show that by first contact with clinical services for psychosis, most people with schizophrenia who will engage in aggressive behaviour may be identified. At first episode, 2 distinct types are distinguishable: those who present a history of antisocial and aggressive behaviour since childhood and those who began engaging in aggressive behaviour as illness onsets. Antipsychotic medications and other treatments shown to be effective for schizophrenia are needed by both types of patients. Additionally, those with a history of antisocial and aggressive behaviour since childhood require cognitive-behavioural programs aimed at reducing these behaviours and promoting prosocial behaviour. Reducing physical victimisation and cannabis use will likely reduce aggressive behaviour. Evidence suggests that threats to hurt others often precede assaults. At first contact with services, patients with schizophrenia who have engaged in aggressive behaviour should be identified and treated for schizophrenia and for aggression. Research is needed to identify interactions between genotypes and environmental factors, from conception onwards, that promote and that protect against the development of aggressive behaviour among persons with schizophrenia.

geneCommittee: a web-based tool for extensively testing the discriminatory power of biologically relevant gene sets in microarray data classification.

PubMed

Reboiro-Jato, Miguel; Arrais, Joel P; Oliveira, José Luis; Fdez-Riverola, Florentino

2014-01-30

The diagnosis and prognosis of several diseases can be shortened through the use of different large-scale genome experiments. In this context, microarrays can generate expression data for a huge set of genes. However, to obtain solid statistical evidence from the resulting data, it is necessary to train and to validate many classification techniques in order to find the best discriminative method. This is a time-consuming process that normally depends on intricate statistical tools. geneCommittee is a web-based interactive tool for routinely evaluating the discriminative classification power of custom hypothesis in the form of biologically relevant gene sets. While the user can work with different gene set collections and several microarray data files to configure specific classification experiments, the tool is able to run several tests in parallel. Provided with a straightforward and intuitive interface, geneCommittee is able to render valuable information for diagnostic analyses and clinical management decisions based on systematically evaluating custom hypothesis over different data sets using complementary classifiers, a key aspect in clinical research. geneCommittee allows the enrichment of microarrays raw data with gene functional annotations, producing integrated datasets that simplify the construction of better discriminative hypothesis, and allows the creation of a set of complementary classifiers. The trained committees can then be used for clinical research and diagnosis. Full documentation including common use cases and guided analysis workflows is freely available at http://sing.ei.uvigo.es/GC/.

Large-Scale medical image analytics: Recent methodologies, applications and Future directions.

PubMed

Zhang, Shaoting; Metaxas, Dimitris

2016-10-01

Despite the ever-increasing amount and complexity of annotated medical image data, the development of large-scale medical image analysis algorithms has not kept pace with the need for methods that bridge the semantic gap between images and diagnoses. The goal of this position paper is to discuss and explore innovative and large-scale data science techniques in medical image analytics, which will benefit clinical decision-making and facilitate efficient medical data management. Particularly, we advocate that the scale of image retrieval systems should be significantly increased at which interactive systems can be effective for knowledge discovery in potentially large databases of medical images. For clinical relevance, such systems should return results in real-time, incorporate expert feedback, and be able to cope with the size, quality, and variety of the medical images and their associated metadata for a particular domain. The design, development, and testing of the such framework can significantly impact interactive mining in medical image databases that are growing rapidly in size and complexity and enable novel methods of analysis at much larger scales in an efficient, integrated fashion. Copyright © 2016. Published by Elsevier B.V.

Interactive visualization for scar transmurality in cardiac resynchronization therapy

NASA Astrophysics Data System (ADS)

Reiml, Sabrina; Toth, Daniel; Panayiotou, Maria; Fahn, Bernhard; Karim, Rashed; Behar, Jonathan M.; Rinaldi, Christopher A.; Razavi, Reza; Rhode, Kawal S.; Brost, Alexander; Mountney, Peter

2016-03-01

Heart failure is a serious disease affecting about 23 million people worldwide. Cardiac resynchronization therapy is used to treat patients suffering from symptomatic heart failure. However, 30% to 50% of patients have limited clinical benefit. One of the main causes is suboptimal placement of the left ventricular lead. Pacing in areas of myocardial scar correlates with poor clinical outcomes. Therefore precise knowledge of the individual patient's scar characteristics is critical for delivering tailored treatments capable of improving response rates. Current research methods for scar assessment either map information to an alternative non-anatomical coordinate system or they use the image coordinate system but lose critical information about scar extent and scar distribution. This paper proposes two interactive methods for visualizing relevant scar information. A 2-D slice based approach with a scar mask overlaid on a 16 segment heart model and a 3-D layered mesh visualization which allows physicians to scroll through layers of scar from endocardium to epicardium. These complementary methods enable physicians to evaluate scar location and transmurality during planning and guidance. Six physicians evaluated the proposed system by identifying target regions for lead placement. With the proposed method more target regions could be identified.

Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases

PubMed Central

Choi, Won-Tak; An, Jing

2014-01-01

Chemokines and their receptors are implicated in a wide range of human diseases, including acquired immune deficiency syndrome (AIDS). The entry of human immunodeficiency virus type 1 (HIV-1) into a cell is initiated by the interaction of the virus’s surface envelope proteins with two cell surface components of the target cell, namely CD4 and a chemokine co-receptor, usually CXCR4 or CCR5. Typical anti-HIV-1 agents include protease and reverse transcriptase inhibitors, but the targets of these agents tend to show rapid mutation rates. As such, strategies based on HIV-1 co-receptors have appeal because they target invariant host determinants. Chemokines and their receptors are also of general interest since they play important roles in numerous physiological and pathological processes in addition to AIDS. Therefore, intensive basic and translational research is ongoing for the dissection of their structure – function relationships in an effort to understand the molecular mechanism of chemokine – receptor interactions and signal transductions across cellular membranes. This paper reviews and discusses recent advances and the translation of new knowledge and discoveries into novel interventional strategies for clinical application. PMID:21565895

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions.

PubMed

Alam, Khondoker; Crowe, Alexandra; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Li, Lang; Yue, Wei

2018-03-14

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs.

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions

PubMed Central

Alam, Khondoker; Crowe, Alexandra; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Li, Lang; Yue, Wei

2018-01-01

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs. PMID:29538325

Dissociable influences of opiates and expectations on pain

PubMed Central

Atlas, Lauren Y.; Whittington, Robert A.; Lindquist, Martin A.; Wielgosz, Joe; Sonty, Nomita; Wager, Tor D.

2012-01-01

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants’ knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference. PMID:22674280

Surgical stent planning: simulation parameter study for models based on DICOM standards.

PubMed

Scherer, S; Treichel, T; Ritter, N; Triebel, G; Drossel, W G; Burgert, O

2011-05-01

Endovascular Aneurysm Repair (EVAR) can be facilitated by a realistic simulation model of stent-vessel-interaction. Therefore, numerical feasibility and integrability in the clinical environment was evaluated. The finite element method was used to determine necessary simulation parameters for stent-vessel-interaction in EVAR. Input variables and result data of the simulation model were examined for their standardization using DICOM supplements. The study identified four essential parameters for the stent-vessel simulation: blood pressure, intima constitution, plaque occurrence and the material properties of vessel and plaque. Output quantities such as radial force of the stent and contact pressure between stent/vessel can help the surgeon to evaluate implant fixation and sealing. The model geometry can be saved with DICOM "Surface Segmentation" objects and the upcoming "Implant Templates" supplement. Simulation results can be stored using the "Structured Report". A standards-based general simulation model for optimizing stent-graft selection may be feasible. At present, there are limitations due to specification of individual vessel material parameters and for simulating the proximal fixation of stent-grafts with hooks. Simulation data with clinical relevance for documentation and presentation can be stored using existing or new DICOM extensions.

Neuropsychiatric Effects of Antimicrobial Agents.

PubMed

Zareifopoulos, Nicholas; Panayiotakopoulos, George

2017-05-01

Antimicrobial drugs used in clinical practice are selected on the basis of their selective toxicity against bacterial cells. However, all exhibit multiple offsite interactions with eukaryotic cell structures, resulting in adverse reactions during antimicrobial pharmacotherapy. A multitude of these side effects involve the nervous system as antimicrobials at clinically relevant concentrations seem to interact with many of the same molecules usually implicated in the action of psychotropic drugs. The importance of such events cannot be overstated, as the misdiagnosis of an adverse drug reaction as a symptom of a primary psychiatric or neurological disorder entails great suffering for the patient affected as well as significant costs for the healthcare system. The neuropsychiatric effects of antimicrobial drugs are extensively documented in the literature. A number of antimicrobial drugs have the potential to exert CNS effects and many are associated with stimulant, psychotomimetic and epileptogenic properties, mediated by GABA antagonism (beta-lactams, quinolones and clarithromycin), NMDA agonism (D-cycloserine, aminoglycosides, and perhaps quinolones), MAO inhibition (linezolid, metronidazole and isoniazid weakly) as well as more exotic mechanisms, as in the case of trimethoprim, isoniazid, ethambutol, rifampicin and the tetracyclines. While those effects are generally undesirable, they may also under certain circumstances be beneficial, and further research is warranted in that direction.

Information needs for making clinical recommendations about potential drug-drug interactions: a synthesis of literature review and interviews.

PubMed

Romagnoli, Katrina M; Nelson, Scott D; Hines, Lisa; Empey, Philip; Boyce, Richard D; Hochheiser, Harry

2017-02-22

Drug information compendia and drug-drug interaction information databases are critical resources for clinicians and pharmacists working to avoid adverse events due to exposure to potential drug-drug interactions (PDDIs). Our goal is to develop information models, annotated data, and search tools that will facilitate the interpretation of PDDI information. To better understand the information needs and work practices of specialists who search and synthesize PDDI evidence for drug information resources, we conducted an inquiry that combined a thematic analysis of published literature with unstructured interviews. Starting from an initial set of relevant articles, we developed search terms and conducted a literature search. Two reviewers conducted a thematic analysis of included articles. Unstructured interviews with drug information experts were conducted and similarly coded. Information needs, work processes, and indicators of potential strengths and weaknesses of information systems were identified. Review of 92 papers and 10 interviews identified 56 categories of information needs related to the interpretation of PDDI information including drug and interaction information; study design; evidence including clinical details, quality and content of reports, and consequences; and potential recommendations. We also identified strengths/weaknesses of PDDI information systems. We identified the kinds of information that might be most effective for summarizing PDDIs. The drug information experts we interviewed had differing goals, suggesting a need for detailed information models and flexible presentations. Several information needs not discussed in previous work were identified, including temporal overlaps in drug administration, biological plausibility of interactions, and assessment of the quality and content of reports. Richly structured depictions of PDDI information may help drug information experts more effectively interpret data and develop recommendations. Effective information models and system designs will be needed to maximize the utility of this information.

Quality of human-computer interaction - results of a national usability survey of hospital-IT in Germany

PubMed Central

2011-01-01

Background Due to the increasing functionality of medical information systems, it is hard to imagine day to day work in hospitals without IT support. Therefore, the design of dialogues between humans and information systems is one of the most important issues to be addressed in health care. This survey presents an analysis of the current quality level of human-computer interaction of healthcare-IT in German hospitals, focused on the users' point of view. Methods To evaluate the usability of clinical-IT according to the design principles of EN ISO 9241-10 the IsoMetrics Inventory, an assessment tool, was used. The focus of this paper has been put on suitability for task, training effort and conformity with user expectations, differentiated by information systems. Effectiveness has been evaluated with the focus on interoperability and functionality of different IT systems. Results 4521 persons from 371 hospitals visited the start page of the study, while 1003 persons from 158 hospitals completed the questionnaire. The results show relevant variations between different information systems. Conclusions Specialised information systems with defined functionality received better assessments than clinical information systems in general. This could be attributed to the improved customisation of these specialised systems for specific working environments. The results can be used as reference data for evaluation and benchmarking of human computer engineering in clinical health IT context for future studies. PMID:22070880

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

PubMed

Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

2016-01-01

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

PubMed Central

Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

2016-01-01

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

Direct measurement of catalase activity in living cells and tissue biopsies.

PubMed

Scaglione, Christine N; Xu, Qijin; Ramanujan, V Krishnan

2016-01-29

Spatiotemporal regulation of enzyme-substrate interactions governs the decision-making steps in biological systems. Enzymes, being functional units of every living cell, contribute to the macromolecular stability of cell survival, proliferation and hence are vital windows to unraveling the biological complexity. Experimental measurements capturing this dynamics of enzyme-substrate interactions in real time add value to this understanding. Furthermore these measurements, upon validation in realistic biological specimens such as clinical biopsies - can further improve our capability in disease diagnostics and treatment monitoring. Towards this direction, we describe here a novel, high-sensitive measurement system for measuring diffusion-limited enzyme-substrate kinetics in real time. Using catalase (enzyme) and hydrogen peroxide (substrate) as the example pair, we demonstrate that this system is capable of direct measurement of catalase activity in vitro and the measured kinetics follows the classical Michaelis-Menten reaction kinetics. We further demonstrate the system performance by measuring catalase activity in living cells and in very small amounts of liver biopsies (down to 1 μg total protein). Catalase-specific enzyme activity is demonstrated by genetic and pharmacological tools. Finally we show the clinically-relevant diagnostic capability of our system by comparing the catalase activities in liver biopsies from young and old mouse (liver and serum) samples. We discuss the potential applicability of this system in clinical diagnostics as well as in intraoperative surgical settings. Copyright © 2016 Elsevier Inc. All rights reserved.

Direct Measurement of Catalase Activity in Living Cells and Tissue Biopsies

PubMed Central

Scaglione, Christine N; Xu, Qijin; Ramanujan, V. Krishnan

2016-01-01

Spatiotemporal regulation of enzyme-substrate interactions governs the decision-making steps in biological systems. Enzymes, being functional units of every living cell, contribute to the macromolecular stability of cell survival, proliferation and hence are vital windows to unraveling the biological complexity. Experimental measurements capturing this dynamics of enzyme-substrate interactions in real time add value to this understanding. Furthermore these measurements, upon validation in realistic biological specimens such as clinical biopsies – can further improve our capability in disease diagnostics and treatment monitoring. Towards this direction, we describe here a novel, high-sensitive measurement system for measuring diffusion-limited enzyme-substrate kinetics in real time. Using catalase (enzyme) and hydrogen peroxide (substrate) as the example pair, we demonstrate that this system is capable of direct measurement of catalase activity in vitro and the measured kinetics follows the classical Michaelis-Menten reaction kinetics. We further demonstrate the system performance by measuring catalase activity in living cells and in very small amounts of liver biopsies (down to 1μg total protein). Catalase-specific enzyme activity is demonstrated by genetic and pharamacological tools. Finally we show the clinically-relevant diagnostic capability of our system by comparing the catalase activities in liver biopsies from young and old mouse (liver and serum) samples. We discuss the potential applicability of this system in clinical diagnostics as well as in intraoperative surgical settings. PMID:26772884

Insulin therapy in diabetes and cancer risk: current understanding and implications for future study: proceedings from a meeting of a European Insulin Safety Consensus Panel, convened and sponsored by Novo Nordisk, held Tuesday October 5, 2010 at The Radisson Edwardian Heathrow Hotel, Hayes, Middlesex, UK.

PubMed

Gough, Stephen C L; Belda-Iniesta, Cristóbal; Poole, Christopher; Weber, Matthias; Russell-Jones, David; Hansen, Bo Falck; Mannucci, Edoardo; Tuomilehto, Jaakko

2011-09-01

Interest in the possibility of certain insulin treatments having the potential to modify cancer development and prognosis was reawakened in 2009, following publication of several epidemiological studies addressing this issue. This interest extends to how diabetes itself and cancer might be linked, and makes desirable an exchange of expert views and knowledge to enhance understanding in this subject among those treating diabetes and cancer, or those developing diabetes therapies. A European meeting was convened with participants invited based on known relevant interests in endocrinology, oncology, epidemiology, and insulin analog design and investigation. Experts in these fields were invited to present on relevant topics, with open discussions held after each presentation. Concern over the potential mitogenic properties of certain insulin analogs has arisen from some (but not all) epidemiological studies, although confounding factors render interpretation controversial. Future epidemiological studies are likely to strengthen confidence in drawing conclusions. Meanwhile, pharmacological studies, and a consideration of cancer pathophysiology, implicate increased insulin-like growth factor-1 receptor affinity, and/or deranged insulin receptor interaction/signaling properties as possible a priori causes for concern with some insulin analogs. Again, interpretation of the body of pharmacological evidence is confounded by the array of test systems and methodologies used, and by studies frequently succumbing to methodological pitfalls. Reassuringly, most available insulin analogs do not differ in their receptor interaction response profile to human insulin, and for those that do there are reasons to question any potential clinical relevance. Nevertheless, it is desirable that new experimental models are devised that can better determine the likely clinical consequences of any variance in receptor response profile versus human insulin. More data are required to increase our understanding of this issue. To facilitate and disseminate such understanding, close cooperation and communication between diabetologists, epidemiologists, oncologists, and insulin engineers will be essential.

Suicide attempts among depressed inpatients with depressive disorder in a Malaysian sample. Psychosocial and clinical risk factors.

PubMed

Chan, L F; Maniam, T; Shamsul, A S

2011-01-01

Depressed inpatients constitute a high-risk population for suicide attempts. To describe the interactions of clinical and psychosocial risk factors influencing suicide attempts among a Malaysian sample of depressed inpatients. Seventy-five subjects were diagnosed with a depressive disorder according to the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinical Version (SCID-CV). Data on suicide attempts, suicidal ideation (Scale for Suicidal Ideation, SSI), depression severity (Beck's Depression Inventory, BDI), recent life-event changes (Social Readjustment Rating Scale, SRRS), sociodemographic and other relevant clinical factors were collected. A third of the subjects presented after a current suicide attempt. Significant factors for a current suicide attempt were race, religion, recent life-event changes, suicidal ideation, and alcohol use disorder. Independent predictive risk factors for a current suicide attempt were Chinese race, recent marital separation, major mortgage or loans, and being newly diagnosed with depression. Any recent change in personal habits was shown to be a protective factor against current suicide attempt. Age and gender were nonsignificant factors. The findings are generally consistent with existing studies and highlight the role of psychosocial risk factors.

Immunological research in clinical psychiatry: report on the consensus debate during the 7th Expert Meeting on Psychiatry and Immunology.

PubMed

Arolt, V; Rothermundt, M; Peters, M; Leonard, B

2002-01-01

There is convincing evidence that cytokines are involved in the physiology and pathophysiology of brain function and interact with different neurotransmitter and neuroendocrine pathways. The possible involvement of the immune system in the neurobiological mechanisms that underlie psychiatric disorders has attracted increasing attention in recent years. Thus in the last decade, numerous clinical studies have demonstrated dysregulated immune functions in patients with psychiatric disorders. Such findings formed the basis of the 7th Expert Meeting on Psychiatry and Immunology in Muenster, Germany, where a consensus symposium was held to consider the strengths and weaknesses of current research in psychoneuroimmunology. Following a general overview of the field, the following topics were discussed: (1) methodological problems in laboratory procedures and recruitment of clinical samples; (2) the importance of pre-clinical research and animal models in psychiatric research; (3) the problem of statistical vs biological relevance. It was concluded that, despite a fruitful proliferation of research activities throughout the last decade, the continuous elaboration of methodological standards including the implementation of hypothesis-driven research represents a task that is likely to prove crucial for the future development of immunology research in clinical psychiatry.

The citrus methoxyflavone tangeretin affects human cell-cell interactions.

PubMed

Brack, Marc E; Boterberg, Tom; Depypere, Herman T; Stove, Christophe; Leclercq, Georges; Mareel, Marc M

2002-01-01

Two effects of the citrus methoxyflavone tangeretin on cell-cell interactions are biologically relevant. Firstly, tangeretin upregulates the function of the E-cadherin/catenin complex in human MCF-7/6 breast carcinoma cells. This leads to firm cell-cell adhesion and inhibition of invasion in vitro. Secondly, tangeretin downregulates the interleukin-2 receptor on T-lymphocytes and natural killer cells. This leads to a decrease in the cytotoxic competence of these immunocytes against cancer cells. The second effect can become important when high doses of tangeretin are combined with adjuvant tamoxifen treatment for breast cancer. Experiments with nude mice bearing MCF-7/6 tumors showed that tangeretin given orally at high doses, abrogated the therapeutic suppression of tumor growth exerted by tamoxifen. No evidence for a tumor promoting effect of tangeretin by itself was found in these experiments. Tangeretin may be an interesting molecule for application in cases where immunosuppression could be clinically beneficial.

Deciphering the complexity of acute inflammation using mathematical models.

PubMed

Vodovotz, Yoram

2006-01-01

Various stresses elicit an acute, complex inflammatory response, leading to healing but sometimes also to organ dysfunction and death. We constructed both equation-based models (EBM) and agent-based models (ABM) of various degrees of granularity--which encompass the dynamics of relevant cells, cytokines, and the resulting global tissue dysfunction--in order to begin to unravel these inflammatory interactions. The EBMs describe and predict various features of septic shock and trauma/hemorrhage (including the response to anthrax, preconditioning phenomena, and irreversible hemorrhage) and were used to simulate anti-inflammatory strategies in clinical trials. The ABMs that describe the interrelationship between inflammation and wound healing yielded insights into intestinal healing in necrotizing enterocolitis, vocal fold healing during phonotrauma, and skin healing in the setting of diabetic foot ulcers. Modeling may help in understanding the complex interactions among the components of inflammation and response to stress, and therefore aid in the development of novel therapies and diagnostics.

Vaccines and Kawasaki disease.

PubMed

Esposito, Susanna; Bianchini, Sonia; Dellepiane, Rosa Maria; Principi, Nicola

2016-01-01

The distinctive immune system characteristics of children with Kawasaki disease (KD) could suggest that they respond in a particular way to all antigenic stimulations, including those due to vaccines. Moreover, treatment of KD is mainly based on immunomodulatory therapy. These factors suggest that vaccines and KD may interact in several ways. These interactions could be of clinical relevance because KD is a disease of younger children who receive most of the vaccines recommended for infectious disease prevention. This paper shows that available evidence does not support an association between KD development and vaccine administration. Moreover, it highlights that administration of routine vaccines is mandatory even in children with KD and all efforts must be made to ensure the highest degree of protection against vaccine-preventable diseases for these patients. However, studies are needed to clarify currently unsolved issues, especially issues related to immunologic interference induced by intravenous immunoglobulin and biological drugs.

[Towards understanding human ecology in nursing practice: a concept analysis].

PubMed

Huynh, Truc; Alderson, Marie

2010-06-01

Human ecology is an umbrella concept encompassing several social, physical, and cultural elements existing in the individual's external environment. The pragmatic utility method was used to analyze the "human ecology" concept in order to ascertain the conceptual fit with nursing epistemology and to promote its use by nurses in clinical practice. Relevant articles for the review were retrieved from the MEDLINE, CINAHL, PsycINFO, and CSA databases using the terms "human ecology," "environment," "nursing," and "ecology." Data analysis revealed that human ecology is perceived as a theoretical perspective designating a complex, multilayered, and multidimensional system, one that comprises individuals and their reciprocal interactions with their global environments and the subsequent impact of these interactions upon their health. Human ecology preconditions include the individuals, their environments, and their transactions. Attributes of this concept encompass the characteristics of an open system (e.g., interdependence, reciprocal).

Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors

NASA Astrophysics Data System (ADS)

Sgrignani, Jacopo; De Luca, Filomena; Torosyan, Hayarpi; Docquier, Jean-Denis; Duan, Da; Novati, Beatrice; Prati, Fabio; Colombo, Giorgio; Grazioso, Giovanni

2016-10-01

β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of 1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.

Cross-cultural adaptation and validation of the Chinese Comfort, Afford, Respect, and Expect scale of caring nurse-patient interaction competence.

PubMed

Chung, Hui-Chun; Hsieh, Tsung-Cheng; Chen, Yueh-Chih; Chang, Shu-Chuan; Hsu, Wen-Lin

2017-11-29

To investigate the construct validity and reliability of the Chinese Comfort, Afford, Respect, and Expect scale, which can be used to determine clinical nurses' competence. The results can also serve to promote nursing competence and improve patient satisfaction. Nurse-patient interaction is critical for improving nursing care quality. However, to date, no relevant validated instrument has been proposed for assessing caring nurse-patient interaction competence in clinical practice. This study adapted and validated the Chinese version of the caring nurse-patient interaction scale. A cross-cultural adaptation and validation study. A psychometric analysis of the four major constructs of the Chinese Comfort, Afford, Respect, and Expect scale was conducted on a sample of 356 nurses from a medical centre in China. Item analysis and exploratory factor analysis were adopted to extract the main components, both the internal consistency and correlation coefficients were used to examine reliability and a confirmatory factor analysis was adopted to verify the construct validity. The goodness-of-fit results of the model were strong. The standardised factor loadings of the Chinese Comfort, Afford, Respect, and Expect scale ranged from 0.73-0.95, indicating that the validity and reliability of this instrument were favourable. Moreover, the 12 extracted items explained 95.9% of the measured content of the Chinese Comfort, Afford, Respect, and Expect scale. The results serve as empirical evidence regarding the validity and reliability of the Chinese Comfort, Afford, Respect, and Expect scale. Hospital nurses increasingly demand help from patients and their family members in identifying health problems and assisting with medical decision-making. Therefore, enhancing nurses' competence in nurse-patient interactions is crucial for nursing and hospital managers to improve nursing care quality. The Chinese caring nurse-patient interaction scale can serve as an effective tool for nursing and hospital managers to evaluate the caring nurse-patient interaction confidence of nurses and improve inpatient satisfaction and quality of care. © 2017 John Wiley & Sons Ltd.

Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876

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

McComas, Casey C.; Palani, Anandan; Chang, Wei

Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinalmore » chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.« less

New Zealand university students' knowledge and attitudes to organ and tissue donation.

PubMed

Cornwall, Jon; Schafer, Cyril; Lal, Navneet; D'Costa, Rohit; Nada-Raja, Shyamala

2015-08-07

Organ and tissue donation (OTD) rates in New Zealand are low compared to many countries. Young adults are 'tomorrow's donors', yet the attitudes and knowledge of this group to OTD have not been examined locally. Such information is relevant to ODT education and clinical engagement. A random sample of University of Otago students (<25 years, permanent New Zealand resident) was surveyed to examine OTD knowledge and attitudes. This included general knowledge, OTD policy (opt-in, opt-out), donation by self, and donation by loved ones. Questions included yes-no, multiple choice, and Likert-type responses. Analyses by sex, demographic characteristics, supportive attitudes to ODT, and University of Otago student profile were performed. 180 responses were gathered (mean age 20.1 years, 67% female, 68% New Zealand European); there were no age or response differences between sexes, participants were generally not representative of the University of Otago student profile. Outcomes indicated limited OTD knowledge, positive support for OTD, and willingness to engage in donation the decision-making process for loved ones. Differences between supportive and non-supportive OTD attitudes was seen for some questions. Findings highlight areas for strategic OTD public engagement and provide details relevant to guiding appropriate clinical interaction in facilitating decisions about OTD.

Mitochondrial Targets for Pharmacological Intervention in Human Disease

PubMed Central

2015-01-01

Over the past several years, mitochondrial dysfunction has been linked to an increasing number of human illnesses, making mitochondrial proteins (MPs) an ever more appealing target for therapeutic intervention. With 20% of the mitochondrial proteome (312 of an estimated 1500 MPs) having known interactions with small molecules, MPs appear to be highly targetable. Yet, despite these targeted proteins functioning in a range of biological processes (including induction of apoptosis, calcium homeostasis, and metabolism), very few of the compounds targeting MPs find clinical use. Recent work has greatly expanded the number of proteins known to localize to the mitochondria and has generated a considerable increase in MP 3D structures available in public databases, allowing experimental screening and in silico prediction of mitochondrial drug targets on an unprecedented scale. Here, we summarize the current literature on clinically active drugs that target MPs, with a focus on how existing drug targets are distributed across biochemical pathways and organelle substructures. Also, we examine current strategies for mitochondrial drug discovery, focusing on genetic, proteomic, and chemogenomic assays, and relevant model systems. As cell models and screening techniques improve, MPs appear poised to emerge as relevant targets for a wide range of complex human diseases, an eventuality that can be expedited through systematic analysis of MP function. PMID:25367773

The relevance of non-human primate and rodent malaria models for humans

PubMed Central

2011-01-01

At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material. PMID:21288352

Use of Digital Rectal Examination as an Adjunct to Prostate Specific Antigen in the Detection of Clinically Significant Prostate Cancer.

PubMed

Halpern, Joshua A; Oromendia, Clara; Shoag, Jonathan E; Mittal, Sameer; Cosiano, Michael F; Ballman, Karla V; Vickers, Andrew J; Hu, Jim C

2018-04-01

Guidelines from the NCCN ® (National Comprehensive Cancer Network®) advocate digital rectal examination screening only in men with elevated prostate specific antigen. We investigated the effect of prostate specific antigen on the association of digital rectal examination and clinically significant prostate cancer in a large American cohort. We evaluated the records of the 35,350 men who underwent digital rectal examination in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial for the development of clinically significant prostate cancer (Gleason 7 or greater). Followup was 343,273 person-years. The primary outcome was the rate of clinically significant prostate cancer among men with vs without suspicious digital rectal examination. We performed competing risks regression to evaluate the interaction between time varying suspicious digital rectal examination and prostate specific antigen. A total of 1,713 clinically significant prostate cancers were detected with a 10-year cumulative incidence of 5.9% (95% CI 5.6-6.2). Higher risk was seen for suspicious vs nonsuspicious digital rectal examination. Increases in absolute risk were small and clinically irrelevant for normal (less than 2 ng/ml) prostate specific antigen (1.5% vs 0.7% risk of clinically significant prostate cancer at 10 years), clinically relevant for elevated (3 ng/ml or greater) prostate specific antigen (23.0% vs 13.7%) and modestly clinically relevant for equivocal (2 to 3 ng/ml) prostate specific antigen (6.5% vs 3.5%). Digital rectal examination demonstrated prognostic usefulness when prostate specific antigen was greater than 3 ng/ml, limited usefulness for less than 2 ng/ml and marginal usefulness for 2 to 3 ng/ml. These findings support the restriction of digital rectal examination to men with higher prostate specific antigen as a reflex test to improve specificity. It should not be used as a primary screening modality to improve sensitivity. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

FDA perspective on specifications for biotechnology products--from IND to PLA.

PubMed

Murano, G

1997-01-01

Quality standards are obligatory throughout development, approval and post-marketing phases of biotechnology-derived products, thus assuring product identity, purity, and potency/strength. The process of developing and setting specifications should be based on sound science and should represent a logical progression of actions based on the use of experiential data spanning manufacturing process validation, consistency in production, and characterization of relevant product properties/attributes, by multiple analytical means. This interactive process occurs in phases, varying in rigour. It is best described as encompassing a framework which starts with the implementation of realistic/practical operational quality limits, progressing to the establishment/adoption of more stringent specifications. The historical database is generated from preclinical, toxicology and early clinical lots. This supports the clinical development programme which, as it progresses, allows for further assay method validation/refinement, adoption/addition due to relevant or newly recognized product attributes or rejection due to irrelevance. In the next phase, (licensing/approval) specifications are set through extended experience and validation of both the preparative and analytical processes, to include availability of suitable reference standards and extensive product characterization throughout its proposed dating period. Subsequent to product approval, the incremental database of test results serves as a natural continuum for further evolving/refining specifications. While there is considerable latitude in the kinds of testing modalities finally adopted to establish product quality on a routine basis, for both drugs and drug products, it is important that the selection takes into consideration relevant (significant) product characteristics that appropriately reflect on identity, purity and potency.

Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

PubMed

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico

2014-01-01

The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

Antibacterial activity of exogenous glutathione and its synergism on antibiotics sensitize carbapenem-associated multidrug resistant clinical isolates of Acinetobacter baumannii.

PubMed

Alharbe, Roaa; Almansour, Ayidh; Kwon, Dong H

2017-10-01

A major clinical impact of A. baumannii is hospital-acquired infections including ventilator-associated pneumonia. The treatment of this pathogen is often difficult due to its innate and acquired resistance to almost all commercially available antibiotics. Infections with carbapenem-associated multidrug resistant A. baumannii is the most problematic. Glutathione is a tripeptide thiol-antioxidant and antibacterial activity of exogenous glutathione was reported in some bacteria. However, clinical relevance and molecular details of the antibacterial activity of glutathione are currently unclear. Seventy clinical isolates of A. baumannii including 63 carbapenem-associated multidrug resistant isolates and a type strain A. baumannii ATCC 19606 were used to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Fractional inhibitory concentration (FIC) and time-killing activity with meropenem and/or glutathione were also determined in the carbapenem-associated multidrug resistant isolates. In addition, the roles of exogenous glutathione in multidrug efflux pumps and β-lactamase production were examined. Levels of MIC and MBC were ranged from 10 to 15mM of exogenous glutathione. All tested carbapenem-associated multidrug resistant isolates were sensitized by all tested antibiotics in combination with subinhibitory concentrations of glutathione. FIC levels of glutathione with carbapenem (meropenem) were all<0.5 and the carbapenem-associated multidrug resistant isolates were killed by subinhibitory concentrations of both glutathione and meropenem at>2log10 within 12h, suggesting glutathione synergistically interacts with meropenem. The roles of multidrug efflux pumps and β-lactamase production were excluded for the glutathione-mediated antibiotic susceptibility. Overall results demonstrate that the antibacterial activity of glutathione is clinically relevant and its synergism on antibiotics sensitizes clinical isolates of A. baumannii regardless of their resistance or susceptibility to antibiotics. This finding suggests that exogenous glutathione alone and/or in combination with existing antibiotics may be applicable to treat infections with carbapenem-associated multidrug resistant A. baumannii. Copyright © 2017 Elsevier GmbH. All rights reserved.

Autism genetics: Methodological issues and experimental design.

PubMed

Sacco, Roberto; Lintas, Carla; Persico, Antonio M

2015-10-01

Autism is a complex neuropsychiatric disorder of developmental origin, where multiple genetic and environmental factors likely interact resulting in a clinical continuum between "affected" and "unaffected" individuals in the general population. During the last two decades, relevant progress has been made in identifying chromosomal regions and genes in linkage or association with autism, but no single gene has emerged as a major cause of disease in a large number of patients. The purpose of this paper is to discuss specific methodological issues and experimental strategies in autism genetic research, based on fourteen years of experience in patient recruitment and association studies of autism spectrum disorder in Italy.

Infection of the endothelium by members of the order Rickettsiales

PubMed Central

Valbuena, Gustavo; Walker, David H.

2010-01-01

Summary The vascular endothelium is the main target of a limited number of infectious agents; Rickettsia, Ehrlichia ruminantium, and Orientia tsutsugamushi are among them. These arthropod-transmitted obligately-intracellular bacteria cause serious systemic diseases that are not infrequently lethal. In this review, we discuss the bacterial biology, vector biology, and clinical aspects of these conditions with particular emphasis on the interactions of these bacteria with the vascular endothelium and how it responds to intracellular infection. The study of these bacteria in relevant in vivo models is likely to offer new insights into the physiology of the endothelium that have not been revealed by other models. PMID:19967137

Micrometastases in neuroblastoma: are they clinically important?

PubMed Central

Burchill, S A

2004-01-01

Despite advances in the treatment of neuroblastoma (NBL), recurrence and metastases continue to pose major problems in clinical management. The relation between micrometastases and the development of secondary disease is not fully understood. However, accurate methods to detect low numbers of tumour cells may allow the evaluation of their role in the disease process, and by implication the possible benefits of eliminating them. Although there is substantial evidence for the increased sensitivity of current molecular methods for the detection of NBL cells compared with more conventional cytology, the clinical relevance and usefulness of detecting this disease remain controversial. The primary goal of current translational research must be to evaluate the clinical relevance of micrometastatic disease detected by these methods in multicentre prospective clinical outcome studies. Only then can the clinical usefulness of these methods be defined so that they may be introduced into relevant clinical practice. PMID:14693828

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

PubMed

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-12-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

PubMed

Olivera, P; Sandborn, W J; Panés, J; Baumann, C; D'Haens, G; Vermeire, S; Danese, S; Peyrin-Biroulet, L

2018-03-01

Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice. © 2018 John Wiley & Sons Ltd.

Animal models of social stress: the dark side of social interactions.

PubMed

Masis-Calvo, Marianela; Schmidtner, Anna K; de Moura Oliveira, Vinícius E; Grossmann, Cindy P; de Jong, Trynke R; Neumann, Inga D

2018-05-10

Social stress occurs in all social species, including humans, and shape both mental health and future interactions with conspecifics. Animal models of social stress are used to unravel the precise role of the main stress system - the HPA axis - on the one hand, and the social behavior network on the other, as these are intricately interwoven. The present review aims to summarize the insights gained from three highly useful and clinically relevant animal models of psychosocial stress: the resident-intruder (RI) test, the chronic subordinate colony housing (CSC), and the social fear conditioning (SFC). Each model brings its own focus: the role of the HPA axis in shaping acute social confrontations (RI test), the physiological and behavioral impairments resulting from chronic exposure to negative social experiences (CSC), and the neurobiology underlying social fear and its effects on future social interactions (SFC). Moreover, these models are discussed with special attention to the HPA axis and the neuropeptides vasopressin and oxytocin, which are important messengers in the stress system, in emotion regulation, as well as in the social behavior network. It appears that both nonapeptides balance the relative strength of the stress response, and simultaneously predispose the animal to positive or negative social interactions.

Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs.

PubMed

Stefanović, Srđan; Janković, Slobodan M; Novaković, Milan; Milosavljević, Marko; Folić, Marko

2018-02-01

Anticonvulsants that belong to the third generation are considered as 'newer' antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol. Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug-drug interactions of the third-generation antiepileptic drugs. Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20-30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated.

Synergistic associations of depression and apolipoprotein E genotype with incidence of dementia.

PubMed

Kim, Jae-Min; Stewart, Robert; Kim, Seon-Young; Kim, Sung-Wan; Bae, Kyung-Yeol; Yang, Su-Jin; Shin, Il-Seon; Yoon, Jin-Sang

2011-09-01

A cohort study of Japanese-American men suggested interactive effects of depression and apolipoprotein E (APOE) e4 allele on risk of incident dementia. In another sample of East Asian origin, we sought to replicate the findings and to explore individual depressive symptoms where this interaction was most evident. Of 625 Korean community elders without dementia at baseline, 518 (83%) were followed over a 2.4-year period and were clinically assessed for incident dementia. Depression was identified by the Geriatric Mental State Schedule (GMS), and nine individual depressive symptoms relevant to DSM-IV major depressive episode criteria were extracted. APOE genotype was ascertained. Covariates included age, gender, education, and disability. There were synergistic interactions between depression and APOE e4 on incident dementia independent of covariates. This interaction was particularly strong for four depressive symptoms: depressed mood, worthlessness, concentration difficulty, and suicidal ideation. We were able to replicate the previous study, finding that, at least in East Asian origin populations, the APOE e4 allele is a stronger predictor of incident dementia in the presence of depressive syndrome, and particular depressive symptoms. Copyright © 2010 John Wiley & Sons, Ltd.

Evaluation of transporters in drug development: Current status and contemporary issues.

PubMed

Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

2017-07-01

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

Acculturative stress and experiential avoidance: relations to depression, suicide, and anxiety symptoms among minority college students.

PubMed

Zvolensky, Michael J; Jardin, Charles; Garey, Lorra; Robles, Zuzuky; Sharp, Carla

2016-11-01

Although college campuses represent strategic locations to address mental health disparity among minorities in the US, there has been strikingly little empirical work on risk processes for anxiety/depression among this population. The present investigation examined the interactive effects of acculturative stress and experiential avoidance in relation to anxiety and depressive symptoms among minority college students (n = 1,095; 78.1% female; Mage = 21.92, SD = 4.23; 15.1% African-American (non-Hispanic), 45.3% Hispanic, 32.5% Asian, and 7.1% other races/ethnicities. Results provided empirical evidence of an interaction between acculturative stress and experiential avoidance for suicidal, social anxiety, and anxious arousal symptoms among the studied sample. Inspection of the significant interactions revealed that acculturative stress was related to greater levels of suicidal symptoms, social anxiety, and anxious arousal among minority college students with higher, but not lower, levels of experiential avoidance. However, in contrast to prediction, there was no significant interaction for depressive symptoms. Together, these data provide novel empirical evidence for the clinically-relevant interplay between acculturative stress and experiential avoidance in regard to a relatively wide array of negative emotional states among minority college students.

Impact of a novel teaching method based on feedback, activity, individuality and relevance on students’ learning

PubMed Central

Brooks, William S.; Laskar, Simone N.; Benjamin, Miles W.; Chan, Philip

2016-01-01

Objectives This study examines the perceived impact of a novel clinical teaching method based on FAIR principles (feedback, activity, individuality and relevance) on students’ learning on clinical placement. Methods This was a qualitative research study. Participants were third year and final year medical students attached to one UK vascular firm over a four-year period (N=108). Students were asked to write a reflective essay on how FAIRness approach differs from previous clinical placement, and its advantages and disadvantages. Essays were thematically analysed and globally rated (positive, negative or neutral) by two independent researchers. Results Over 90% of essays reported positive experiences of feedback, activity, individuality and relevance model.  The model provided multifaceted feedback; active participation; longitudinal improvement; relevance to stage of learning and future goals; structured teaching; professional development; safe learning environment; consultant involvement in teaching. Students perceived preparation for tutorials to be time intensive for tutors/students; a lack of teaching on medical sciences and direct observation of performance; more than once weekly sessions would be beneficial; some issues with peer and public feedback, relevance to upcoming exam and large group sizes. Students described negative experiences of “standard” clinical teaching. Conclusions Progressive teaching programmes based on the FAIRness principles, feedback, activity, individuality and relevance, could be used as a model to improve current undergraduate clinical teaching. PMID:26995588

Social defeat interacts with Disc1 mutations in the mouse to affect behavior.

PubMed

Haque, F Nipa; Lipina, Tatiana V; Roder, John C; Wong, Albert H C

2012-08-01

DISC1 (Disrupted-in-schizophrenia 1) is a strong candidate susceptibility gene for psychiatric disease that was originally discovered in a family with a chromosomal translocation severing this gene. Although the family members with the translocation had an identical genetic mutation, their clinical diagnosis and presentation varied significantly. Gene-environment interactions have been proposed as a mechanism underlying the complex heritability and variable phenotype of psychiatric disorders such as major depressive disorder and schizophrenia. We hypothesized that gene-environment interactions would affect behavior in a mutant Disc1 mouse model. We examined the effect of chronic social defeat (CSD) as an environmental stressor in two lines of mice carrying different Disc1 point mutations, on behaviors relevant to psychiatric illness: locomotion in a novel open field (OF), pre-pulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI), elevated plus maze (EPM), forced swim test (FST), sucrose consumption (SC), and the social interaction task for sociability and social novelty (SSN). We found that Disc1-L100P +/- and wild-type mice have similar anxiety responses to CSD, while Q31L +/- mice had a very different response. We also found evidence of significant gene-environment interactions in the OF, EPM and SSN. Copyright © 2012 Elsevier B.V. All rights reserved.

Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model.

PubMed

Matosin, Natalie; Halldorsdottir, Thorhildur; Binder, Elisabeth B

2018-05-15

Epidemiologic and genetic studies suggest common environmental and genetic risk factors for a number of psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Genetic and environmental factors, especially adverse life events, not only have main effects on disease development but also may interact to shape risk and resilience. Such gene by adversity interactions have been described for FKBP5, an endogenous regulator of the stress-neuroendocrine system, conferring risk for a number of psychiatric disorders. In this review, we present a molecular and cellular model of the consequences of FKBP5 by early adversity interactions. We illustrate how altered genetic and epigenetic regulation of FKBP5 may contribute to disease risk by covering evidence from clinical and preclinical studies of FKBP5 dysregulation, known cell-type and tissue-type expression patterns of FKBP5 in humans and animals, and the role of FKBP5 as a stress-responsive molecular hub modulating many cellular pathways. FKBP5 presents the possibility to better understand the molecular and cellular factors contributing to a disease-relevant gene by environment interaction, with implications for the development of biomarkers and interventions for psychiatric disorders. Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers.

PubMed

Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Bâldea, Ioan; Leucuţa, Sorin E

2011-08-01

The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.

Clinically Relevant Outcome Measures Following Limb Osseointegration; Systematic Review of the Literature.

PubMed

Al Muderis, Munjed M; Lu, William Y; Li, Jiao Jiao; Kaufman, Kenton; Orendurff, Michael; Highsmith, M Jason; Lunseth, Paul A; Kahle, Jason T

2018-02-01

The current standard of care for an amputee is a socket-based prostheses. An osseointegrated implant (OI) is an alternative for prosthetic attachment. Osseointegration addresses reported problems related to wearing a socket interface, such as skin issues, discomfort, diminished function, quality of life, prosthetic use, and abandonment. The purpose of this report is to systematically review current literature regarding OI to identify and categorize the reported clinically relevant outcome measures, rate the quality of available evidence, and synthesize the findings. A multidisciplinary team used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methods. Search methodology was based on identifying clinically relevant articles. Three databases were searched: PubMed, CINAHL, and Web of Science. Clinical studies with aggregated data reporting at least 1 clinically relevant outcome measure were included. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criterion was used for critical appraisal and recommendations. This review identified 21 clinically relevant observational studies. Outcome measures were categorized into the following 9 categories: vibratory stimulation, complications, biomechanics, economics, patient-reported outcome measures, electromyography, x-ray, physical functional performance, and energy consumption. This systematic review consisted of Level III and IV observational studies. Homogeneous outcome measures with strong psychometric properties across prospective studies do not exist to date. Higher-level, prospective, randomized, long-term, clinically relevant trials are needed to prove efficacy of OI compared with socket prosthetic attachment. Osseointegration was at least equivalent to sockets in most studies. In some cases, it was superior. Osseointegration represents a promising alternative to socket prosthetic attachments for extremity amputees. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

DNA Repair in Prostate Cancer: Biology and Clinical Implications.

PubMed

Mateo, Joaquin; Boysen, Gunther; Barbieri, Christopher E; Bryant, Helen E; Castro, Elena; Nelson, Pete S; Olmos, David; Pritchard, Colin C; Rubin, Mark A; de Bono, Johann S

2017-03-01

For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer. We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa.

PubMed

Gamero-Villarroel, Carmen; González, Luz M; Rodríguez-López, Raquel; Albuquerque, David; Carrillo, Juan A; García-Herráiz, Angustias; Flores, Isalud; Gervasini, Guillermo

2017-09-01

TFAP2B and KCTD15 are obesity-related genes that interact to regulate feeding behavior. We hypothesize that variability in these loci, isolated or in combination, could also be related to the risk of eating disorders (ED) and/or associated psychological traits. We screened 425 participants (169 ED patients, 75 obese subjects, and 181 controls) for 10 clinically relevant and tag single-nucleotide polymorphisms (SNPs) in KCTD15 and TFAP2B by the Sequenom MassARRAY platform and direct sequencing. Psychometric evaluation was performed with EDI-2 and SCL-90R inventories. The KCTD15 rs287103 T variant allele was associated with increased risk of bulimia nervosa (BN) (OR = 4.34 [1.47-29.52]; p  = .003) and with scores of psychopathological scales of these patients. Haplotype *6 in KCTD15 was more frequent in controls (OR = 0.40 [0.20-0.80], p  = .009 for anorexia nervosa), while haplotype *4 in TFAP2B affected all three scales of the SCL-90R inventory in BN patients ( p  ≤ .01). Epistasis analyses revealed relevant interactions with body mass index of BN patients ( p  < .001). Genetic profiles in obese patients did not significantly differ from those found in ED patients. This is the first study that evaluates the combined role of TFAP2B and KCTD15 genes in ED. Our preliminary findings suggest that the interaction of genetic variability in these loci could influence the risk for ED and/or anthropometric and psychological parameters.

A network analysis of DSM-5 posttraumatic stress disorder symptoms and correlates in U.S. military veterans.

PubMed

Armour, Cherie; Fried, Eiko I; Deserno, Marie K; Tsai, Jack; Pietrzak, Robert H

2017-01-01

Recent developments in psychometrics enable the application of network models to analyze psychological disorders, such as PTSD. Instead of understanding symptoms as indicators of an underlying common cause, this approach suggests symptoms co-occur in syndromes due to causal interactions. The current study has two goals: (1) examine the network structure among the 20 DSM-5 PTSD symptoms, and (2) incorporate clinically relevant variables to the network to investigate whether PTSD symptoms exhibit differential relationships with suicidal ideation, depression, anxiety, physical functioning/quality of life (QoL), mental functioning/QoL, age, and sex. We utilized a nationally representative U.S. military veteran's sample; and analyzed the data from a subsample of 221 veterans who reported clinically significant DSM-5 PTSD symptoms. Networks were estimated using state-of-the-art regularized partial correlation models. Data and code are published along with the paper. The 20-item DSM-5 PTSD network revealed that symptoms were positively connected within the network. Especially strong connections emerged between nightmares and flashbacks; blame of self or others and negative trauma-related emotions, detachment and restricted affect; and hypervigilance and exaggerated startle response. The most central symptoms were negative trauma-related emotions, flashbacks, detachment, and physiological cue reactivity. Incorporation of clinically relevant covariates into the network revealed paths between self-destructive behavior and suicidal ideation; concentration difficulties and anxiety, depression, and mental QoL; and depression and restricted affect. These results demonstrate the utility of a network approach in modeling the structure of DSM-5 PTSD symptoms, and suggest differential associations between specific DSM-5 PTSD symptoms and clinical outcomes in trauma survivors. Implications of these results for informing the assessment and treatment of this disorder, are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Drug Information Services Today: Current Role and Future Perspectives in Rational Drug Therapy.

PubMed

Amundstuen Reppe, Linda; Spigset, Olav; Schjøtt, Jan

2016-02-01

Polypharmacy and complex drug treatment regimens are becoming increasingly common, which may lead to adverse drug reactions, drug interactions, medication nonadherence, and increasing costs and thus challenge the rational use of drugs. At the same time, the accessibility of drug information increases, and health care professionals may have limited opportunities and capabilities to search and critically evaluate drug information. Clinicians have reported difficulties in searching the best evidence and translating study findings into clinically meaningful information applicable to specific patients. Consequently, it remains a challenge to ensure the rational use of drugs in the years to come. Drug information centers (DICs) have been established to promote the rational use of drugs. One of the most important tasks of DICs is the question and answer services for health care professionals posing drug-related questions. DICs staffed by pharmacists and clinical pharmacologists hold expertise in searching for drug information and critical evaluation of the literature. The uniqueness in this service lies not only in the identification and interpretation of the scientific literature but also in the adaptation of the findings into specific clinical situations and the discussion of possible solutions with the enquirer. Thus, DICs could provide valuable decision support to the clinic. Taking into account the increasing number of possible drug-related questions that will arise today and in the future, the DICs will remain highly relevant in the years to come. However, the DICs must follow the developments in health information technology to disseminate relevant, unbiased drug information to old and new users of the service. Moreover, the DICs are important tools to counterbalance the drug information published by the pharmaceutical industry. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Bone formation at recombinant human bone morphogenetic protein-2-coated titanium implants in the posterior mandible (Type II bone) in dogs.

PubMed

Wikesjö, Ulf M E; Xiropaidis, Andreas V; Qahash, Mohammed; Lim, Won Hee; Sorensen, Rachel G; Rohrer, Michael D; Wozney, John M; Hall, Jan

2008-11-01

Conventional oral/maxillofacial implants reach osseointegration over several months during which the titanium fixtures interact with alveolar bone. The objective of this study was to determine if adsorbing recombinant human bone morphogenetic protein-2 (rhBMP-2) onto a titanium porous oxide (TPO) implant surface might enhance or accelerate local bone formation and support osseointegration in a large animal oral/maxillofacial orthotopic model. Endosseous implants with a TPO surface were installed into the edentulated posterior mandible in eight adult Hound Labrador mongrel dogs. The implant surface had been adsorbed with rhBMP-2 at 0.2 or 4.0 mg/ml. TPO implants without rhBMP-2 served as control. Treatments were randomized between jaw quadrants. Mucosal flaps were advanced and sutured leaving the implants submerged. Clinical and radiographic evaluations were made immediately post-surgery, at day 10 (suture removal), and week 4 and 8 post-surgery. The animals received fluorescent bone markers at week 3, 4, and at week 8 post-surgery, when they were euthanized for histologic analysis. TPO implants coated with rhBMP-2 exhibited dose-dependent bone remodelling including immediate resorption and formation of implant adjacent bone, and early establishment of clinically relevant osseointegration. The resulting bone-implant contact, although clinically respectable, appeared significantly lower for rhBMP-2-coated implants compared with the control [rhBMP-2 (0.2 mg/ml) 43.3+/-10.8%versus 71.7+/-7.8%, p<0.02; rhBMP-2 (4.0 mg/ml) 35.4+/-10.6%versus 68.2+/-11.0%, p<0.03]. rhBMP-2 adsorbed onto TPO implant surfaces initiates dose-dependent peri-implant bone re-modelling resulting in the formation of normal, physiologic bone and clinically relevant osseointegration within 8 weeks.

Design principles for cancer therapy guided by changes in complexity of protein-protein interaction networks.

PubMed

Benzekry, Sebastian; Tuszynski, Jack A; Rietman, Edward A; Lakka Klement, Giannoula

2015-05-28

The ever-increasing expanse of online bioinformatics data is enabling new ways to, not only explore the visualization of these data, but also to apply novel mathematical methods to extract meaningful information for clinically relevant analysis of pathways and treatment decisions. One of the methods used for computing topological characteristics of a space at different spatial resolutions is persistent homology. This concept can also be applied to network theory, and more specifically to protein-protein interaction networks, where the number of rings in an individual cancer network represents a measure of complexity. We observed a linear correlation of R = -0.55 between persistent homology and 5-year survival of patients with a variety of cancers. This relationship was used to predict the proteins within a protein-protein interaction network with the most impact on cancer progression. By re-computing the persistent homology after computationally removing an individual node (protein) from the protein-protein interaction network, we were able to evaluate whether such an inhibition would lead to improvement in patient survival. The power of this approach lied in its ability to identify the effects of inhibition of multiple proteins and in the ability to expose whether the effect of a single inhibition may be amplified by inhibition of other proteins. More importantly, we illustrate specific examples of persistent homology calculations, which correctly predict the survival benefit observed effects in clinical trials using inhibitors of the identified molecular target. We propose that computational approaches such as persistent homology may be used in the future for selection of molecular therapies in clinic. The technique uses a mathematical algorithm to evaluate the node (protein) whose inhibition has the highest potential to reduce network complexity. The greater the drop in persistent homology, the greater reduction in network complexity, and thus a larger potential for survival benefit. We hope that the use of advanced mathematics in medicine will provide timely information about the best drug combination for patients, and avoid the expense associated with an unsuccessful clinical trial, where drug(s) did not show a survival benefit.

An Evaluation of the Interactive Query Expansion in an Online Library Catalogue with a Graphical User Interface.

ERIC Educational Resources Information Center

Hancock-Beaulieu, Micheline; And Others

1995-01-01

An online library catalog was used to evaluate an interactive query expansion facility based on relevance feedback for the Okapi, probabilistic, term weighting, retrieval system. A graphical user interface allowed searchers to select candidate terms extracted from relevant retrieved items to reformulate queries. Results suggested that the…

Professional Interaction, Relevant Practical Experience, and Intellectual Contributions at Nondoctoral AACSB-Accredited Accounting Programs

ERIC Educational Resources Information Center

Arlinghaus, Barry P.

2008-01-01

In this article, the author discusses a survey of faculty members at nondoctoral AACSB-accredited accounting programs in the United States. The purpose of the survey was to determine the environment for professional interaction and relevant experience in light of institutional demands for intellectual contributions. The findings show that the…

Ultrasound guidance in regional anesthesia: state of the art review through challenging clinical scenarios

PubMed Central

Sites, Brian D; Antonakakis, John G

2009-01-01

Ultrasound guided regional anesthesia (UGRA) for peripheral nerve blockade is becoming increasingly popular. The advantage of ultrasound technology is that it affords the anesthesiologist the real time ability to visualize neural structures, needle advancement, and local anesthetic spread. Recent data suggest that UGRA generates improved success rates and reductions in performance times in comparison to traditional approaches. Further, the use of ultrasound technology in peripheral nerve blocks has provided insight into needle–nerve interactions, revealing distinct limitations of nerve stimulator techniques. Given that UGRA requires a unique set of skills, formal standards and guidelines are currently being developed by leadership societies in order to foster education and training. This review article, in a case vignette format, highlights important techniques, concepts, and limitations regarding the use of ultrasound to facilitate regional anesthesia. Clinically relevant aspects of ultrasound physics are also discussed. PMID:22915860

Integrating query of relational and textual data in clinical databases: a case study.

PubMed

Fisk, John M; Mutalik, Pradeep; Levin, Forrest W; Erdos, Joseph; Taylor, Caroline; Nadkarni, Prakash

2003-01-01

The authors designed and implemented a clinical data mart composed of an integrated information retrieval (IR) and relational database management system (RDBMS). Using commodity software, which supports interactive, attribute-centric text and relational searches, the mart houses 2.8 million documents that span a five-year period and supports basic IR features such as Boolean searches, stemming, and proximity and fuzzy searching. Results are relevance-ranked using either "total documents per patient" or "report type weighting." Non-curated medical text has a significant degree of malformation with respect to spelling and punctuation, which creates difficulties for text indexing and searching. Presently, the IR facilities of RDBMS packages lack the features necessary to handle such malformed text adequately. A robust IR+RDBMS system can be developed, but it requires integrating RDBMSs with third-party IR software. RDBMS vendors need to make their IR offerings more accessible to non-programmers.

Design, clinical translation and immunological response of biomaterials in regenerative medicine

NASA Astrophysics Data System (ADS)

Sadtler, Kaitlyn; Singh, Anirudha; Wolf, Matthew T.; Wang, Xiaokun; Pardoll, Drew M.; Elisseeff, Jennifer H.

2016-07-01

The field of regenerative medicine aims to replace tissues lost as a consequence of disease, trauma or congenital abnormalities. Biomaterials serve as scaffolds for regenerative medicine to deliver cells, provide biological signals and physical support, and mobilize endogenous cells to repair tissues. Sophisticated chemistries are used to synthesize materials that mimic and modulate native tissue microenvironments, to replace form and to elucidate structure-function relationships of cell-material interactions. The therapeutic relevance of these biomaterial properties can only be studied after clinical translation, whereby key parameters for efficacy can be defined and then used for future design. In this Review, we present the development and translation of biomaterials for two tissue engineering targets, cartilage and cornea, both of which lack the ability to self-repair. Finally, looking to the future, we discuss the role of the immune system in regeneration and the potential for biomaterial scaffolds to modulate immune signalling to create a pro-regenerative environment.

[Rhabdomyolysis in a Bipolar Adolescent. Analysis of Associated Factors].

PubMed

Restrepo, Diana; Montoya, Pablo; Giraldo, Laura; Gaviria, Génesis; Mejía, Catalina

2015-01-01

To describe a case of rhabdomyolysis associated with the use of quetiapine and lamotrigine in an adolescent treated for bipolar disorder. Description of the clinical case, analysis of the associated factors and a non-systematic review of the relevant literature. An 18 year old male, with bipolar disorder and treated pharmacologically with quetiapine and lamotrigine, after two weeks of physical activity presents with rhabdomyolysis. Quetiapine and exercise have been associated with rhabdomyolysis. The mediator mechanism of this association has not been found, although it has been established that there is neuromuscular dysfunction and an increase in sarcomere permeability. This clinical case allowed the complex interaction between antipsychotic agents and increased physical activity to be observed in a psychiatric adolescent patient, as well as the appearance of a potentially lethal medical complication. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Factors related to drug approvals: predictors of outcome?

PubMed

Liberti, Lawrence; Breckenridge, Alasdair; Hoekman, Jarno; McAuslane, Neil; Stolk, Pieter; Leufkens, Hubert

2017-06-01

There is growing interest in characterising factors associated with positive regulatory outcomes for drug marketing authorisations. We assessed empirical studies published over the past 15 years seeking to identify predictive factors. Factors were classified to one of four 'factor clusters': evidentiary support; product or indication characteristics; company experience or strategy; social and regulatory factors. We observed a heterogeneous mix of technical factors (e.g., study designs, clinical evidence of efficacy) and less studied social factors (e.g., company-regulator interactions). We confirmed factors known to be of relevance to drug approval decisions (imperative) and a cohort of less understood (compensatory) social factors. Having robust supportive clinical evidence, addressing rare or serious illness, following scientific advice and prior company experience were associated with positive outcomes, which illustrated the multifactorial nature of regulatory decision making and factors need to be considered holistically while having varying, context-dependent importance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Patient Summary and medicines reconciliation: application of the ISO/CEN EN 13606 standard in clinical practice.

PubMed

Farfán Sedano, Francisco J; Terrón Cuadrado, Marta; Castellanos Clemente, Yolanda; Serrano Balazote, Pablo; Moner Cano, David; Robles Viejo, Montserrat

2011-01-01

The comparison of the patient's current medication list with the medication being ordered when admitted to Hospital, identifying omissions, duplications, dosing errors, and potential interactions, constitutes the core process of medicines reconciliation. Access to the medication the patient is taking at home could be unfeasible as this information is frequently stored in various locations and in diverse proprietary formats. The lack of interoperability between those information systems, namely the Primary Care and the Specialized Electronic Health Records (EHRs), facilitates medication errors and endangers patient safety. Thus, the development of a Patient Summary that includes clinical data from different electronic systems will allow doctors access to relevant information enabling a safer and more efficient assistance. Such a collection of data from heterogeneous and distributed systems has been achieved in this Project through the construction of a federated view based on the ISO/CEN EN13606 Standard for architecture and communication of EHRs.

Comparison of three commercial knowledge bases for detection of drug-drug interactions in clinical decision support.

PubMed

Fung, Kin Wah; Kapusnik-Uner, Joan; Cunningham, Jean; Higby-Baker, Stefanie; Bodenreider, Olivier

2017-07-01

To compare 3 commercial knowledge bases (KBs) used for detection and avoidance of potential drug-drug interactions (DDIs) in clinical practice. Drugs in the DDI tables from First DataBank (FDB), Micromedex, and Multum were mapped to RxNorm. The KBs were compared at the clinical drug, ingredient, and DDI rule levels. The KBs were evaluated against a reference list of highly significant DDIs from the Office of the National Coordinator for Health Information Technology (ONC). The KBs and the ONC list were applied to a prescription data set to simulate their use in clinical decision support. The KBs contained 1.6 million (FDB), 4.5 million (Micromedex), and 4.8 million (Multum) clinical drug pairs. Altogether, there were 8.6 million unique pairs, of which 79% were found only in 1 KB and 5% in all 3 KBs. However, there was generally more agreement than disagreement in the severity rankings, especially in the contraindicated category. The KBs covered 99.8-99.9% of the alerts of the ONC list and would have generated 25 (FDB), 145 (Micromedex), and 84 (Multum) alerts per 1000 prescriptions. The commercial KBs differ considerably in size and quantity of alerts generated. There is less variability in severity ranking of DDIs than suggested by previous studies. All KBs provide very good coverage of the ONC list. More work is needed to standardize the editorial policies and evidence for inclusion of DDIs to reduce variation among knowledge sources and improve relevance. Some DDIs considered contraindicated in all 3 KBs might be possible candidates to add to the ONC list. Published by Oxford University Press on behalf of the American Medical Informatics Association 2017. This work is written by US Government employees and is in the public domain in the United States.

Clinical outcomes of patients with diabetes and atrial fibrillation treated with apixaban: results from the ARISTOTLE trial.

PubMed

Ezekowitz, Justin A; Lewis, Basil S; Lopes, Renato D; Wojdyla, Daniel M; McMurray, John J V; Hanna, Michael; Atar, Dan; Cecilia Bahit, M; Keltai, Matyas; Lopez-Sendon, Jose L; Pais, Prem; Ruzyllo, Witold; Wallentin, Lars; Granger, Christopher B; Alexander, John H

2015-04-01

We compared clinical outcomes in patients with AF with and without diabetes in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. The main efficacy endpoints were SSE and mortality; safety endpoints were major and major/clinically relevant non-major bleeding. A total of 4547/18 201 (24.9%) patients had diabetes who were younger (69 vs. 70 years), more had coronary artery disease (39 vs. 31%), and higher mean CHADS2 (2.9 vs. 1.9) and HAS-BLED scores (1.9 vs. 1.7) (all P < 0.0001) than patients without diabetes. Patients with diabetes receiving apixaban had lower rates of SSE [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.53-1.05), all-cause mortality (HR 0.83, 95% CI 0.67-1.02), cardiovascular mortality (HR 0.89, 95% CI 0.66-1.20), intra-cranial haemorrhage (HR 0.49, 95% CI 0.25-0.95), and a similar rate of myocardial infarction (HR 1.02, 95% CI 0.62-1.67) compared with warfarin. For major bleeding, a quantitative interaction was seen (P-interaction = 0.003) with a greater reduction in major bleeding in patients without diabetes even after multivariable adjustment. Other measures of bleeding showed a consistent reduction with apixaban compared with warfarin without a significant interaction based on diabetes status. Apixaban has similar benefits on reducing stroke, decreasing mortality, and causing less intra-cranial bleeding than warfarin in patients with and without diabetes. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Barriers to Advance Care Planning at the End of Life: An Explanatory Systematic Review of Implementation Studies

PubMed Central

Lund, Susi; Richardson, Alison; May, Carl

2015-01-01

Context Advance Care Plans (ACPs) enable patients to discuss and negotiate their preferences for the future including treatment options at the end of life. Their implementation poses significant challenges. Objective To investigate barriers and facilitators to the implementation of ACPs, focusing on their workability and integration in clinical practice. Design An explanatory systematic review of qualitative implementation studies. Data sources Empirical studies that reported interventions designed to support ACP in healthcare. Web of Knowledge, Ovid MEDLINE, CINAHL, PsycINFO, British Nursing Index and PubMed databases were searched. Methods Direct content analysis, using Normalization Process Theory, to identify and characterise relevant components of implementation processes. Results 13 papers identified from 166 abstracts were included in the review. Key factors facilitating implementation were: specially prepared staff utilizing a structured approach to interactions around ACPs. Barriers to implementation were competing demands of other work, the emotional and interactional nature of patient-professional interactions around ACPs, problems in sharing decisions and preferences within and between healthcare organizations. Conclusions This review demonstrates that doing more of the things that facilitate delivery of ACPs will not reduce the effects of those things that undermine them. Structured tools are only likely to be partially effective and the creation of a specialist cadre of ACP facilitators is unlikely to be a sustainable solution. The findings underscore both the challenge and need to find ways to routinely incorporate ACPs in clinical settings where multiple and competing demands impact on practice. Interventions most likely to meet with success are those that make elements of Advance Care Planning workable within complex and time pressured clinical workflows. PMID:25679395

Drug metabolism and pharmacokinetic diversity of ranunculaceae medicinal compounds.

PubMed

Hao, Da-Cheng; Ge, Guang-Bo; Xiao, Pei-Gen; Wang, Ping; Yang, Ling

2015-01-01

The wide-reaching distributed angiosperm family Ranunculaceae has approximately 2200 species in around 60 genera. Chemical components of this family include several representative groups: benzylisoquinoline alkaloid (BIA), ranunculin, triterpenoid saponin and diterpene alkaloid, etc. Their extensive clinical utility has been validated by traditional uses of thousands of years and current evidence-based medicine studies. Drug metabolism and pharmacokinetic (DMPK) studies of plant-based natural products are an indispensable part of comprehensive medicinal plant exploration, which could facilitate conservation and sustainable utilization of Ranunculaceae pharmaceutical resources, as well as new chemical entity development with improved DMPK parameters. However, DMPK characteristics of Ranunculaceaederived medicinal compounds have not been summarized. Black cohosh (Cimicifuga) and goldenseal (Hydrastis) raise concerns of herbdrug interaction. DMPK studies of other Ranunculaceae genera, e.g., Nigella, Delphinium, Aconitum, Trollius, and Coptis, are also rapidly increasing and becoming more and more clinically relevant. In this contribution, we highlight the up-to-date awareness, as well as the challenges around the DMPK-related issues in optimization of drug development and clinical practice of Ranunculaceae compounds. Herb-herb interaction of Ranunculaceae herb-containing traditional Chinese medicine (TCM) formula could significantly influence the in vivo pharmacokinetic behavior of compounds thereof, which may partially explain the complicated therapeutic mechanism of TCM formula. Although progress has been made on revealing the absorption, distribution, metabolism, excretion and toxicity (ADME/T) of Ranunculaceae compounds, there is a lack of DMPK studies of traditional medicinal genera Aquilegia, Thalictrum and Clematis. Fluorescent probe compounds could be promising substrate, inhibitor and/or inducer in future DMPK studies of Ranunculaceae compounds. A better understanding of the important herb-drug/herb-herb interactions, bioavailability and metabolomics aspects of Ranunculaceae compounds will bolster future natural product-based drug design and the comprehensive investigation of inter-individual inconsistency of drug metabolism.

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

PubMed

Antonijevic, Nebojsa M; Zivkovic, Ivana D; Jovanovic, Ljubica M; Matic, Dragan M; Kocica, Mladen J; Mrdovic, Igor B; Kanjuh, Vladimir I; Culafic, Milica D

2017-01-01

The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution.

PubMed

Chakrabarti, Shaon; Michor, Franziska

2017-07-15

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR . ©2017 American Association for Cancer Research.

Impact of Interactive e-Learning Modules on Appropriateness of Imaging Referrals: A Multicenter, Randomized, Crossover Study.

PubMed

Velan, Gary M; Goergen, Stacy K; Grimm, Jane; Shulruf, Boaz

2015-11-01

Health care expenditure on diagnostic imaging investigations is increasing, and many tests are ordered inappropriately. Validated clinical decision rules (CDRs) for certain conditions are available to aid in assessing the need for imaging. However, awareness and utilization of CDRs are lacking. This study compared the efficacy and perceived impact of interactive e-learning modules versus static versions of CDRs, for learning about appropriate imaging referrals. A multicenter, randomized, crossover trial was performed; participants were volunteer medical students and recent graduates. In week 1, group 1 received an e-learning module on appropriate imaging referrals for pulmonary embolism; group 2 received PDF versions of relevant CDRs, and an online quiz with feedback. In week 2, the groups crossed over, focusing on imaging referrals for cervical spine trauma in adults. Online assessments were administered to both groups at the end of each week, and participants completed an online questionnaire at the end of the trial. Group 1 (e-learning module) performed significantly better on the pulmonary embolism knowledge assessment. After the crossover, participants in group 2 (e-learning module) were significantly more likely to improve their scores in the assessment of cervical spine trauma knowledge. Both groups gave positive evaluations of the e-learning modules. Interactive e-learning was significantly more effective for learning in this cohort, compared with static CDRs. We believe that the authentic clinical scenarios, feedback, and integration provided by the e-learning modules contributed to their impact. This study has implications for implementation of e-learning tools to facilitate appropriate referrals for imaging investigations in clinical practice. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies.

PubMed

Waddington, Claire S; Darton, Thomas C; Woodward, William E; Angus, Brian; Levine, Myron M; Pollard, Andrew J

2014-05-01

Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host-pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Extracellular vesicles in parasitic diseases

PubMed Central

Marcilla, Antonio; Martin-Jaular, Lorena; Trelis, Maria; de Menezes-Neto, Armando; Osuna, Antonio; Bernal, Dolores; Fernandez-Becerra, Carmen; Almeida, Igor C.; del Portillo, Hernando A.

2014-01-01

Parasitic diseases affect billions of people and are considered a major public health issue. Close to 400 species are estimated to parasitize humans, of which around 90 are responsible for great clinical burden and mortality rates. Unfortunately, they are largely neglected as they are mainly endemic to poor regions. Of relevance to this review, there is accumulating evidence of the release of extracellular vesicles (EVs) in parasitic diseases, acting both in parasite–parasite inter-communication as well as in parasite–host interactions. EVs participate in the dissemination of the pathogen and play a role in the regulation of the host immune systems. Production of EVs from parasites or parasitized cells has been described for a number of parasitic infections. In this review, we provide the most relevant findings of the involvement of EVs in intercellular communication, modulation of immune responses, involvement in pathology, and their potential as new diagnostic tools and therapeutic agents in some of the major human parasitic pathogens. PMID:25536932

Data Science in the Research Domain Criteria Era: Relevance of Machine Learning to the Study of Stress Pathology, Recovery, and Resilience

PubMed Central

Galatzer-Levy, Isaac R.; Ruggles, Kelly; Chen, Zhe

2017-01-01

Diverse environmental and biological systems interact to influence individual differences in response to environmental stress. Understanding the nature of these complex relationships can enhance the development of methods to: (1) identify risk, (2) classify individuals as healthy or ill, (3) understand mechanisms of change, and (4) develop effective treatments. The Research Domain Criteria (RDoC) initiative provides a theoretical framework to understand health and illness as the product of multiple inter-related systems but does not provide a framework to characterize or statistically evaluate such complex relationships. Characterizing and statistically evaluating models that integrate multiple levels (e.g. synapses, genes, environmental factors) as they relate to outcomes that a free from prior diagnostic benchmarks represents a challenge requiring new computational tools that are capable to capture complex relationships and identify clinically relevant populations. In the current review, we will summarize machine learning methods that can achieve these goals. PMID:29527592

Treatment resistance and psychodynamic psychiatry: concepts psychiatry needs from psychoanalysis.

PubMed

Plakun, Eric

2012-06-01

Over the last 30 years psychiatry and psychoanalysis have moved in substantially divergent directions. Psychiatry has become rich in methodology but conceptually limited, with a drift toward biological reductionism. Psychoanalysis has remained relatively limited in methodology, but conceptually rich. The rich methodology of psychiatry has led to major contributions in discovering gene by environment interactions, the importance of early adversity, and to recognition of the serious problem posed by treatment resistance. However, psychiatry's biologically reductionistic conceptual focus interferes with the development of a nuanced clinical perspective based on emerging knowledge that might help more treatment resistant patients become treatment responders. This article argues that recognition of the problem of treatment resistance in psychiatry creates a need for it to reconnect with the conceptual richness of psychoanalysis in order to improve patient care. Psychodynamic psychiatry is defined as the relevant intersection of psychiatry and psychoanalysis where this reconnection can occur. I will suggest selected aspects of psychoanalysis that are especially relevant to psychiatry in improving outcomes in work with treatment resistant patients.

Genome-wide analysis of pain-, nerve- and neurotrophin -related gene expression in the degenerating human annulus

PubMed Central

2012-01-01

Background In spite of its high clinical relevance, the relationship between disc degeneration and low back pain is still not well understood. Recent studies have shown that genome-wide gene expression studies utilizing ontology searches provide an efficient and valuable methodology for identification of clinically relevant genes. Here we use this approach in analysis of pain-, nerve-, and neurotrophin-related gene expression patterns in specimens of human disc tissue. Control, non-herniated clinical, and herniated clinical specimens of human annulus tissue were studied following Institutional Review Board approval. Results Analyses were performed on more generated (Thompson grade IV and V) discs vs. less degenerated discs (grades I-III), on surgically operated discs vs. control discs, and on herniated vs. control discs. Analyses of more degenerated vs. less degenerated discs identified significant upregulation of well-recognized pain-related genes (bradykinin receptor B1, calcitonin gene-related peptide and catechol-0-methyltransferase). Nerve growth factor was significantly upregulated in surgical vs. control and in herniated vs. control discs. All three analyses also found significant changes in numerous proinflammatory cytokine- and chemokine-related genes. Nerve, neurotrophin and pain-ontology searches identified many matrix, signaling and functional genes which have known importance in the disc. Immunohistochemistry was utilized to confirm the presence of calcitonin gene-related peptide, catechol-0-methyltransferase and bradykinin receptor B1 at the protein level in the human annulus. Conclusions Findings point to the utility of microarray analyses in identification of pain-, neurotrophin and nerve-related genes in the disc, and point to the importance of future work exploring functional interactions between nerve and disc cells in vitro and in vivo. Nerve, pain and neurotrophin ontology searches identified numerous changes in proinflammatory cytokines and chemokines which also have significant relevance to disc biology. Since the degenerating human disc is primarily an avascular tissue site into which disc cells have contributed high levels of proinflammatory cytokines, these substances are not cleared from the tissue and remain there over time. We hypothesize that as nerves grow into the human annulus, they encounter a proinflammatory cytokine-rich milieu which may sensitize nociceptors and exacerbate pain production. PMID:22963171

Mechanisms and disease relevance of neutrophil extracellular trap formation.

PubMed

Van Avondt, Kristof; Hartl, Dominik

2018-03-15

While the microscopic appearance of neutrophil extracellular traps (NETs) has fascinated basic researchers since its discovery, the (patho)physiological mechanisms triggering NET release, the disease relevance and clinical translatability of this unconventional cellular mechanism remained poorly understood. Here, we summarize and discuss current concepts of the mechanisms and disease relevance of NET formation. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

Clinical Relevance of IgE to Profilin and/or Polcalcin in Pollen-Sensitized Patients.

PubMed

San Nicoló, Marion; Braun, Thomas; Eder, Katharina; Berghaus, Alexander; Gröger, Moritz

2016-01-01

Component-resolved diagnostics is gaining importance in allergy diagnostics. Allergen extracts contain components with different rates of prevalence and clinical relevance, which can be subdivided at molecular level into major and minor allergens. Clinical complaints are usually triggered by major allergens, while the role of sensitization to the panallergens profilin and polcalcin still remains unclear. Eighty-six patients from southern Bavaria with sensitization to the panallergens profilin (Bet v 2/Phl p 12) and/or polcalcin (Bet v 4/Phl p 7) were examined in regard to their sensitization to the 4 main botanic denominations Betulaceae, Oleaceae, Poaceae and Asteraceae by skin prick test and measurement of specific immunoglobulin E antibodies to natural allergen extracts as well as major allergen components rPhl p 1/5, rBet v 1, rOle e 1 and nArt v 1. Sensitization was rated as clinically relevant or irrelevant depending on anamnesis or intranasal allergen challenge. Regarding the 4 botanic denominations, there was no significant difference in the incidence of sensitization to the panallergens profilin, polcalcin or both. The sensitization pattern does not alter when subdividing the cohort into clinically relevant and silent sensitization. We did not find clinically symptomatic sensitization to panallergens without cosensitization to a major allergen. Our results suggest that sole sensitization to panallergens seems to have no clinical relevance in allergic rhinoconjunctivitis. Clinical complaints seem to be triggered manly by major allergens. Thus, component-resolved allergy diagnostics is crucial in the diagnosis and treatment of polysensitized patients. © 2016 S. Karger AG, Basel.

Fluid-structure interaction including volumetric coupling with homogenised subdomains for modeling respiratory mechanics.

PubMed

Yoshihara, Lena; Roth, Christian J; Wall, Wolfgang A

2017-04-01

In this article, a novel approach is presented for combining standard fluid-structure interaction with additional volumetric constraints to model fluid flow into and from homogenised solid domains. The proposed algorithm is particularly interesting for investigations in the field of respiratory mechanics as it enables the mutual coupling of airflow in the conducting part and local tissue deformation in the respiratory part of the lung by means of a volume constraint. In combination with a classical monolithic fluid-structure interaction approach, a comprehensive model of the human lung can be established that will be useful to gain new insights into respiratory mechanics in health and disease. To illustrate the validity and versatility of the novel approach, three numerical examples including a patient-specific lung model are presented. The proposed algorithm proves its capability of computing clinically relevant airflow distribution and tissue strain data at a level of detail that is not yet achievable, neither with current imaging techniques nor with existing computational models. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Insight into the fundamental interactions between LEDGF binding site inhibitors and integrase combining docking and molecular dynamics simulations.

PubMed

De Luca, Laura; Morreale, Francesca; Chimirri, Alba

2012-12-21

In recent years, HIV-1 integrase (IN) has emerged as an attractive target for novel anti-AIDS agents. In particular, nonactive-site-binding IN inhibitors would display synergy with current strand-transfer-specific IN inhibitors and other antiretroviral drugs in clinical use. An effective allosteric inhibitory approach would be the disruption of protein-protein interaction (PPI) between IN and cellular cofactors, such as LEDGF/p75. To date, several small molecules have been reported to be inhibitors of the PPI between IN and LEDGF/p75. In this study, we investigated the most relevant interactions between five selected PPI inhibitors and IN comparing them to the naturally occurring IN-LEDGF/p75 complex. We calculated the binding free energies by using the method of molecular mechanics-generalized Born surface area (MM-GBSA). Total energy was decomposed on per residue contribution, and hydrogen bond occupancies were monitored throughout the simulations. Considering all these results we obtained a good correlation with experimental activity and useful insights for the development of new inhibitors.

The Organophosphate Paraoxon and Its Antidote Obidoxime Inhibit Thrombin Activity and Affect Coagulation In Vitro

PubMed Central

Golderman, Valery; Shavit-Stein, Efrat; Tamarin, Ilia; Rosman, Yossi; Shrot, Shai; Rosenberg, Nurit

2016-01-01

Organophosphates (OPs) are potentially able to affect serine proteases by reacting with their active site. The potential effects of OPs on coagulation factors such as thrombin and on coagulation tests have been only partially characterized and potential interactions with OPs antidotes such as oximes and muscarinic blockers have not been addressed. In the current study, we investigated the in vitro interactions between coagulation, thrombin, the OP paraoxon, and its antidotes obidoxime and atropine. The effects of these substances on thrombin activity were measured in a fluorescent substrate and on coagulation by standard tests. Both paraoxon and obidoxime but not atropine significantly inhibited thrombin activity, and prolonged prothrombin time, thrombin time, and partial thromboplastin time. When paraoxon and obidoxime were combined, a significant synergistic effect was found on both thrombin activity and coagulation tests. In conclusion, paraoxon and obidoxime affect thrombin activity and consequently alter the function of the coagulation system. Similar interactions may be clinically relevant for coagulation pathways in the blood and possibly in the brain. PMID:27689805

[Perioperative adverse events related to antidepressive agents use].

PubMed

Rozec, B; Cinotti, R; Blanloeil, Y

2011-11-01

Depression is the most common psychiatric disease, which is treated by the use of antidepressive agents possessing various mechanisms of action. Thus, the use in preoperative period of antidepressive agents is frequent (7% of patients scheduled for surgery). The objective of this review was to update the knowledge on the drug interactions between antidepressive agents and drugs used in perioperative period. (i) Medline and Ovid databases using combination of antidepressive agent and perioperative period as keywords; (ii) national and European epidemiologic database; (iii) expert recommendation and official French health agency; (iv) reference book chapters. The clinical practice showed a limited risk of adverse event related to antidepressant agents interaction with perioperative used drugs. In the two past decades, few relevant observations of adverse event related with imipramine and monoamine oxidase inhibitors use was reported. The most recent antidepressive agents had no serious adverse interaction. Nevertheless, the serotonin syndrome has to be known as far as it is more and more reported. In case of hypotension, the use of vasopressive agent has to be careful because of excessive response. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug–Drug Interaction Between Clopidogrel and Dasabuvir

PubMed Central

Fu, W; Badri, P; Bow, DAJ; Fischer, V

2017-01-01

Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug–drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl‐β‐D glucuronide metabolite of which has been reported as a strong mechanism‐based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl‐β‐D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5–1.9‐fold for Cmax and 1.9–2.8‐fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant. PMID:28411400

Gene-Gene and Gene-Environment Interactions in Ulcerative Colitis

PubMed Central

Wang, Ming-Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M. Ilyas; Rebert, Nancy; Duerr, Richard H.; Achkar, Jean-Paul

2014-01-01

Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high order interactions. Exploratory genotype correlations with UC sub-phenotypes (extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)) were conducted. The combination of 133 UC loci yielded good UC risk predictability (area under the curve [AUC] of 0.86). A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P=3.26E-05). Explained UC variance increased from 37% to 42% after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions. PMID:24241240

Interviews with children about their mental health problems: The congruence and validity of information that children report.

PubMed

Macleod, Emily; Woolford, June; Hobbs, Linda; Gross, Julien; Hayne, Harlene; Patterson, Tess

2017-04-01

To obtain a child's perspective during a mental health assessment, he or she is usually interviewed. Although researchers and clinicians generally agree that it is beneficial to hear a child's account of his or her presenting issues, there is debate about whether children provide reliable or valid clinical information during these interviews. Here, we examined whether children provide clinically and diagnostically relevant information in a clinical setting. In all, 31 children aged 5-12-years undergoing mental health assessments were asked open-ended questions about their presenting problems during a semi-structured interview. We coded the information that children reported to determine whether it was clinically relevant and could be used to diagnose their problems and to formulate and plan treatment. We also coded children's information to determine whether it was congruent with the children's presenting problems and their eventual clinical diagnoses. Most of the information that children reported was clinically relevant and included information about behaviour, affect, temporal details, thoughts, people, the environment, and the child's physical experiences. The information that children reported was also clinically valid; it was congruent with the problems that were discussed (84%) and also with the eventual diagnosis that the child received after a complete assessment (74%). We conclude that children can contribute relevant, clinically useful, valid information during clinical psychological assessments.

Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.

PubMed

Loi, Sherene; Sirtaine, Nicolas; Piette, Fanny; Salgado, Roberto; Viale, Giuseppe; Van Eenoo, Françoise; Rouas, Ghizlane; Francis, Prudence; Crown, John P A; Hitre, Erika; de Azambuja, Evandro; Quinaux, Emmanuel; Di Leo, Angelo; Michiels, Stefan; Piccart, Martine J; Sotiriou, Christos

2013-03-01

Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.

Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions

PubMed Central

Lin, Aijing; Liu, Kang K. L.; Bartsch, Ronny P.; Ivanov, Plamen Ch.

2016-01-01

Within the framework of ‘Network Physiology’, we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain–heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain–heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems. PMID:27044991

Update of green tea interactions with cardiovascular drugs and putative mechanisms.

PubMed

Werba, José Pablo; Misaka, Shingen; Giroli, Monica Gianna; Shimomura, Kenju; Amato, Manuela; Simonelli, Niccolò; Vigo, Lorenzo; Tremoli, Elena

2018-04-01

Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions. Copyright © 2018. Published by Elsevier B.V.

Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions

NASA Astrophysics Data System (ADS)

Lin, Aijing; Liu, Kang K. L.; Bartsch, Ronny P.; Ivanov, Plamen Ch.

2016-05-01

Within the framework of `Network Physiology', we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain-heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain-heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems.

Estrogen Receptor Folding Modulates cSrc Kinase SH2 Interaction via a Helical Binding Mode.

PubMed

Nieto, Lidia; Tharun, Inga M; Balk, Mark; Wienk, Hans; Boelens, Rolf; Ottmann, Christian; Milroy, Lech-Gustav; Brunsveld, Luc

2015-11-20

The estrogen receptors (ERs) feature, next to their transcriptional role, important nongenomic signaling actions, with emerging clinical relevance. The Src Homology 2 (SH2) domain mediated interaction between cSrc kinase and ER plays a key role in this; however the molecular determinants of this interaction have not been elucidated. Here, we used phosphorylated ER peptide and semisynthetic protein constructs in a combined biochemical and structural study to, for the first time, provide a quantitative and structural characterization of the cSrc SH2-ER interaction. Fluorescence polarization experiments delineated the SH2 binding motif in the ER sequence. Chemical shift perturbation analysis by nuclear magnetic resonance (NMR) together with molecular dynamics (MD) simulations allowed us to put forward a 3D model of the ER-SH2 interaction. The structural basis of this protein-protein interaction has been compared with that of the high affinity SH2 binding sequence GpYEEI. The ER features a different binding mode from that of the "two-pronged plug two-hole socket" model in the so-called specificity determining region. This alternative binding mode is modulated via the folding of ER helix 12, a structural element directly C-terminal of the key phosphorylated tyrosine. The present findings provide novel molecular entries for understanding nongenomic ER signaling and targeting the corresponding disease states.

Human Liver Cytochrome P450 3A4 Ubiquitination

PubMed Central

Wang, YongQiang; Kim, Sung-Mi; Trnka, Michael J.; Liu, Yi; Burlingame, A. L.; Correia, Maria Almira

2015-01-01

CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site-directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum-associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate recruitment, an important step in CYP3A4 proteasomal degradation. PMID:25451919

Locating relevant patient information in electronic health record data using representations of clinical concepts and database structures.

PubMed

Pan, Xuequn; Cimino, James J

2014-01-01

Clinicians and clinical researchers often seek information in electronic health records (EHRs) that are relevant to some concept of interest, such as a disease or finding. The heterogeneous nature of EHRs can complicate retrieval, risking incomplete results. We frame this problem as the presence of two gaps: 1) a gap between clinical concepts and their representations in EHR data and 2) a gap between data representations and their locations within EHR data structures. We bridge these gaps with a knowledge structure that comprises relationships among clinical concepts (including concepts of interest and concepts that may be instantiated in EHR data) and relationships between clinical concepts and the database structures. We make use of available knowledge resources to develop a reproducible, scalable process for creating a knowledge base that can support automated query expansion from a clinical concept to all relevant EHR data.

Selecting relevant and feasible measurement instruments for the revised Dutch clinical practice guideline for physical therapy in patients after stroke.

PubMed

Otterman, Nicoline; Veerbeek, Janne; Schiemanck, Sven; van der Wees, Philip; Nollet, Frans; Kwakkel, Gert

2017-07-01

To select relevant and feasible instruments for the revision of the Dutch clinical practice guideline for physical therapy in patients with stroke. In this implementation study a comprehensive proposal for ICF categories and matching instruments was developed, based on reliability and validity. Relevant instruments were then selected in a consensus round by 11 knowledge brokers who were responsible for the implementation of the selected instruments. The feasibility of the selected instruments was tested by 36 physical therapists at different work settings within stroke services. Finally, instruments that were deemed relevant and feasible were included in the revised guideline. A total of 28 instruments were recommended for inclusion in the revised guideline. Nineteen instruments were retained from the previous guideline. Ten new instruments were tested in clinical practice, seven of which were found feasible. Two more instruments were added after critical appraisal of the set of the measurement instruments. The revised guideline contains 28 relevant and feasible instrument selected and tested in clinical practice by physical therapists. Further education and implementation is needed to integrate instruments in clinical practice. Further research is proposed for developing and implementing a core set of measurement instruments to be used at fixed time points to establish data registries that allow for continuous improvement of rehabilitation for stroke patients. Implications for Rehabilitation The revised Dutch Stroke Physical Therapy Guideline recommends a total of 28 instruments, that are relevant and feasible for clinical practice of physical therapist in the different settings of stroke rehabilitation. The selection of instrument in daily practice should be part of the clinical reasoning process of PTs and be tailored to individual patients' needs and the degree of priority of the affected ICF category. Suggested education strategies for further integration of instruments in of the daily practice of PTs in Stroke Rehabilitation are: 'Training on the job' and 'peer assessment in clinical situations'.

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

PubMed Central

Zhao, Yuqi; Chen, Jing; Freudenberg, Johannes M.; Meng, Qingying; Rajpal, Deepak K.; Yang, Xia

2017-01-01

Objective Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. Approach and Results We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. Conclusions Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD. PMID:26966275

The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

Cancer.gov

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine. PMID:18505911

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

PubMed Central

Gufford, Brandon T.; Chen, Gang; Vergara, Ana G.; Lazarus, Philip; Oberlies, Nicholas H.

2015-01-01

Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4′- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27–66 µM; UGT1A1, 3.2–8.3 µM; UGT1A8, 19–73 µM; and UGT1A10, 65–120 µM) encompassed reported intestinal tissue concentrations (20–310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product–drug interactions in the context of cancer prevention. PMID:26070840

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

PubMed

Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

2015-09-01

Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Retrieving clinical evidence: a comparison of PubMed and Google Scholar for quick clinical searches.

PubMed

Shariff, Salimah Z; Bejaimal, Shayna Ad; Sontrop, Jessica M; Iansavichus, Arthur V; Haynes, R Brian; Weir, Matthew A; Garg, Amit X

2013-08-15

Physicians frequently search PubMed for information to guide patient care. More recently, Google Scholar has gained popularity as another freely accessible bibliographic database. To compare the performance of searches in PubMed and Google Scholar. We surveyed nephrologists (kidney specialists) and provided each with a unique clinical question derived from 100 renal therapy systematic reviews. Each physician provided the search terms they would type into a bibliographic database to locate evidence to answer the clinical question. We executed each of these searches in PubMed and Google Scholar and compared results for the first 40 records retrieved (equivalent to 2 default search pages in PubMed). We evaluated the recall (proportion of relevant articles found) and precision (ratio of relevant to nonrelevant articles) of the searches performed in PubMed and Google Scholar. Primary studies included in the systematic reviews served as the reference standard for relevant articles. We further documented whether relevant articles were available as free full-texts. Compared with PubMed, the average search in Google Scholar retrieved twice as many relevant articles (PubMed: 11%; Google Scholar: 22%; P<.001). Precision was similar in both databases (PubMed: 6%; Google Scholar: 8%; P=.07). Google Scholar provided significantly greater access to free full-text publications (PubMed: 5%; Google Scholar: 14%; P<.001). For quick clinical searches, Google Scholar returns twice as many relevant articles as PubMed and provides greater access to free full-text articles.

Discrepancies between explicit and implicit self-esteem and their relationship to symptoms of depression and mania.

PubMed

Pavlickova, Hana; Turnbull, Oliver H; Bentall, Richard P

2014-09-01

Self-esteem is a key feature of bipolar symptomatology. However, so far no study has examined the interaction between explicit and implicit self-esteem in individuals vulnerable to bipolar disorder. Cross-sectional design was employed. Thirty children of parents with bipolar disorder and 30 offspring of control parents completed Hamilton Rating Scale for Depression, the Bech-Rafaelson Mania Scale, the Self-esteem Rating Scale and the Implicit Association Test. No differences between groups were revealed in levels of explicit or implicit self-esteem. However, bipolar offspring showed increased levels of symptoms of depression and mania. Furthermore, depressive symptoms were associated with low explicit self-esteem, whilst symptoms of mania were associated with low implicit self-esteem. When self-esteem discrepancies were examined, damaged self-esteem (i.e., low explicit but high implicit self-esteem) was associated with depression, whilst no associations between mania and self-esteem discrepancies were found. Not only explicit, but also implicit self-esteem, and the interactions between the two are of relevance in bipolar symptoms. Clinical implications and future research directions are discussed. Explicit as well as implicit SE, and particularly their relationship, are relevant for mental health. Fluctuations in implicit SE may serve as an early indicator for risk of bipolarity. Psychotherapeutic approaches may be more suitable for one kind of SE challenge than the other. © 2013 The British Psychological Society.

Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

PubMed Central

Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

2015-01-01

Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs

PubMed Central

Moore, Nicholas; Pollack, Charles; Butkerait, Paul

2015-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

Children's behavioral inhibition and anxiety disorder symptom severity: The role of individual differences in respiratory sinus arrhythmia.

PubMed

Viana, Andres G; Palmer, Cara A; Zvolensky, Michael J; Alfano, Candice A; Dixon, Laura J; Raines, Elizabeth M

2017-06-01

Although behavioral inhibition (BI) is clearly identified as a temperamental risk factor for childhood anxiety psychopathology, much less is known about whether the strength of this association may vary as a function of parasympathetic nervous system regulation in children with anxiety disorders. To build upon extant research in this area, the present study examined whether respiratory sinus arrhythmia (RSA) can explicate the conditions in which BI is linked to increased symptom severity among anxiety-disordered children (N = 44; M = 9.61 years, SD = 1.63; 52% female and African American, respectively). We examined RSA responding both during a basal period and during a stressor ("challenge" RSA): interacting with a "mystery guest" who was wearing a mask. As hypothesized, the interaction between BI and both basal and challenge RSA was significantly related to anxiety disorder symptom severity, even after controlling for depressive symptoms. The form of the interaction indicated that highest levels of anxiety disorder symptoms were found among children with high levels of BI and low basal and challenge RSA, respectively. These data provide novel empirical evidence of a clinically-relevant interplay between RSA and BI in relation to anxiety disorder symptom severity among clinical youth. Future work is needed to expand on the specific mechanisms that may be responsible e for the interplay between temperamental and psychobiological risks for childhood anxiety. Copyright © 2017 Elsevier Ltd. All rights reserved.

Barriers and enablers for the development and implementation of allied health clinical practice guidelines in South African primary healthcare settings: a qualitative study.

PubMed

Dizon, J M; Grimmer, K; Louw, Q; Machingaidze, S; Parker, H; Pillen, H

2017-09-15

The South African allied health (AH) primary healthcare (PHC) workforce is challenged with the complex rehabilitation needs of escalating patient numbers. The application of evidence-based care using clinical practice guidelines (CPGs) is one way to make efficient and effective use of resources. Although CPGs are common for AH in high-income countries, there is limited understanding of how to do this in low- to middle-income countries. This paper describes barriers and enablers for AH CPG uptake in South African PHC. Semi-structured individual interviews were undertaken with 25 South African AH managers, policymakers, clinicians and academics to explore perspectives on CPGs. Interviews were conducted by researcher dyads, one being familiar with South African AH PHC practice and the other with CPG expertise. Rigour and transparency of data collection was ensured. Interview transcripts were analysed by structuring content into codes, categories and themes. Exemplar quotations were extracted to support themes. CPGs were generally perceived to be relevant to assist AH providers to address the challenges of consistently providing evidence-based care in South African PHC settings. CPGs were considered to be tools for managing clinical, social and economic complexities of AH PHC practice, particularly if CPG recommendations were contextusalised. CPG uptake was one way to deal with increasing pressures to make efficient use of scarce financial resources, and to demonstrate professional legitimacy. Themes comprised organisational infrastructures and capacities for CPG uptake, interactions between AH actors and interaction with broader political structures, the nature of AH evidence in CPGs, and effectively implementing CPGs into practice. CPGs contextualised to local circumstances offer South African PHC AH services with an efficient vehicle for putting evidence into practice. There are challenges to doing this, related to local barriers such as geography, AH training, workforce availability, scarce resources, an escalating number of patients requiring complex rehabilitation, and local knowledge. Concerted attempts to implement locally relevant CPGs for AH primary care in South Africa are required to improve widespread commitment to evidence-based care, as well as to plan efficient and effective service delivery models.

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects

PubMed Central

Mohamed, Khadeeja; Goyal, Navin; Bouhired, Samia; Hussaini, Azra; Jones, Siôn W.; Koh, Gavin C. K. W.; Kostov, Ivan; Taylor, Maxine; Wolstenholm, Allen; Duparc, Stephan

2016-01-01

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0–∞) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0–last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.) PMID:27697758

Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects.

PubMed

Green, Justin A; Mohamed, Khadeeja; Goyal, Navin; Bouhired, Samia; Hussaini, Azra; Jones, Siôn W; Koh, Gavin C K W; Kostov, Ivan; Taylor, Maxine; Wolstenholm, Allen; Duparc, Stephan

2016-12-01

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (C max ) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine C max by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC 0-∞ ) by 12% (1 to 26%), and the half-life (t 1/2 ) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC 0-last ). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.). Copyright © 2016 Green et al.

The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies.

PubMed

Patterson, Sara E; Liu, Rangjiao; Statz, Cara M; Durkin, Daniel; Lakshminarayana, Anuradha; Mockus, Susan M

2016-01-16

Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer-associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in-house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology.

Delineation of the interactions between the chemotherapeutic agent eribulin mesylate (E7389) and human CYP3A4.

PubMed

Zhang, Z-Y; King, B M; Pelletier, R D; Wong, Y N

2008-09-01

Eribulin mesylate (E7389), a structurally simplified, synthetic analog of the marine natural product halichondrin B, acts by inhibiting microtubule dynamics via mechanisms distinct from those of other tubulin-targeted agents. Eribulin is currently in Phase III clinical trials for the treatment of metastatic breast cancer. Since drug-induced modulation of cytochrome P450 enzymes, particularly CYP3A4, is a frequent cause of drug-drug interactions, we examined the effects of eribulin on the activity and expression of hepatic and recombinant CYP3A4 (rCYP3A4) in vitro. Identification of the enzyme(s) responsible for eribulin metabolism was based on compound depletion and metabolite formation in reaction mixtures containing subcellular liver fractions or primary human hepatocytes, plus recombinant Phases I and II metabolic enzymes. The role of the enzyme(s) identified was confirmed using enzyme-selective inhibitors and the correlation with prototypic enzyme activity. The effect of eribulin on enzymatic activity was characterized using both microsomal preparations and recombinant enzymes, while the possible modulation of protein expression was evaluated in primary cultures of human hepatocytes. Eribulin was primarily metabolized by CYP3A4, resulting in the formation of at least four monooxygenated metabolites. In human liver microsomal preparations, eribulin suppressed the activities of CYP3A4-mediated testosterone and midazolam hydroxylation with an apparent K (i) of approximately 20 microM. Eribulin competitively inhibited the testosterone 6beta-hydroxylation, nifedipine dehydration, and R-warfarin 10-hydroxylation activities of rCYP3A4, with an average apparent K (i) of approximately 10 microM. These inhibitions were reversible, with no apparent mechanism-based inactivation. Eribulin did not induce the expression or activities of CYP1A and CYP3A enzymes in human primary hepatocytes, and clinically relevant concentrations of eribulin did not inhibit CYP3A4-mediated metabolism of various therapeutic agents, including carbamazepine, diazepam, paclitaxel, midazolam, tamoxifen, or terfenadine. Eribulin was predominantly metabolized by CYP3A4. Although eribulin competitively inhibited the testosterone 6beta-hydroxylation, nifedipine dehydration, and R-warfarin 10-hydroxylation activities of rCYP3A4, it did not induce or inhibit hepatic CYP3A4 activity at clinically relevant concentrations. As eribulin does not appear to affect the metabolism of other therapeutic agents by CYP3A4, our data suggest that eribulin would not be expected to inhibit the metabolism of concurrently administered drugs that are metabolized by CYP3A4, suggesting a minimal risk of drug-drug interactions in the clinical setting.

Urokinase-receptor (u-PAR): an essential player in multiple games of cancer: a review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease.

PubMed

Laufs, Stephanie; Schumacher, Jens; Allgayer, Heike

2006-08-01

The relevance of the u-PA system in mediating tumor-associated proteolysis, invasion and metastasis, amongst other phenomena associated with tumor progression, has been clearly demonstrated in diverse cancer entities. This review will update on the biological and clinical relevance of the urokinase-receptor (u-PAR). Specifically, the article focuses on the potential importance of u-PAR for the development of minimal residual disease in solid cancer, and in this context reviews the biological relevance of the u-PAR for tumor cell dormancy. Furthermore, transcriptional mechanisms regulating u-PAR in vitro and in vivo, and their potential clinical and therapeutic relevance in gastrointestinal cancers, are elucidated.