How to handle the delayed or the missed dose of edoxaban in patients with non-valvular atrial fibrillation: model-informed remedial strategy

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

Exploring Relation between Cognitive Perceptual Deficits and Functional Performance in Schizophrenia- A Mini Review

Schizophrenia is a serious mental illness that affects how a person thinks, feels and behaves. People with schizophrenia may seem like they have lost touch with reality, which causes significant distress for the individual, their family members and friends. If left untreated, symptoms of schizophrenia can be persistent and disabling. Cognitive perceptual impairment is a core feature of schizophrenia and several studies have demonstrated that it is strongly related with daily functioning and other functional outcomes. Several RCTs have demonstrated that patients with schizophrenia improve negative symptomatology after cognitive rehabilitation. The prevalence of schizophrenia affects patient’s participation in functional tasks. The aim of this review was to explore literature; published in the past 15 years in the area of cognitive perceptual deficits in schizophrenia and functional impairments caused due to it. We also explored the strategies for remediation. In this integrated mini review, published researches were reviewed including RCTs, observational studies, interventional , experimental, correlational studies, case reports and systematic reviews. To conclude, it was analyzed that dysfunctions in working memory, attention and abstract thinking and problem solving have been extensively documented in schizophrenia, which may improve slightly with remedial strategies.

Strategies for achieving customer order flexibility – supplier perspective

PurposeThe purpose of this study is to develop a framework of strategies to achieving customer order flexibility in and related to the order-to-delivery (OTD) process. The purpose is also to investigate how companies prioritize various strategies to achieve customer order flexibility.Design/methodology/approachBased on a literature review, pre-tests and conceptual reasoning, a conceptual framework of strategies related to the order-to-delivery process was developed. The strategies were linked to the order quantity and delivery lead-time flexibility dimensions. This structure resulted in six groups covering enabling as well as remedial strategies. An empirical interview study of ten customer–supplier relationships was conducted.FindingsThe interviews identified additional strategies, thereby expanding the framework. The enabling strategies with the highest median values were “have continuous contact with the customer's purchaser” and “use safety stock of raw materials/semi-finished products”. The remedial strategy with the highest median was “re-plan/re-prioritize the order backlog”. In the delivery sub-process, it was more common to apply remedial strategies for delivery lead-time than for order quantities.Research limitations/implicationsThe developed framework is a contribution to the literature on operational flexibility in and related to the OTD process. It complements existing knowledge by taking a supplier perspective.Practical implicationsSuppliers can use the framework as a tool to understand and systematically achieve better customer order flexibility in and related to the OTD process. Customers can use the framework as a checklist for supplier evaluation and supplier development.Originality/valueFew identified studies include empirical data on customer order flexibility.

Campylobacter Biofilms: Potential of Natural Compounds to Disrupt Campylobacter jejuni Transmission

Microbial biofilms occur naturally in many environmental niches and can be a significant reservoir of infectious microbes in zoonotically transmitted diseases such as that caused by Campylobacter jejuni, the leading cause of acute human bacterial gastroenteritis world-wide. The greatest challenge in reducing the disease caused by this organism is reducing transmission of C. jejuni to humans from poultry via the food chain. Biofilms enhance the stress tolerance and antimicrobial resistance of the microorganisms they harbor and are considered to play a crucial role for Campylobacter spp. survival and transmission to humans. Unconventional approaches to control biofilms and to improve the efficacy of currently used antibiotics are urgently needed. This review summarizes the use plant- and microorganism-derived antimicrobial and antibiofilm compounds such as essential oils, antimicrobial peptides (AMPs), polyphenolic extracts, algae extracts, probiotic-derived factors, d-amino acids (DAs) and glycolipid biosurfactants with potential to control biofilms formed by Campylobacter, and the suggested mechanisms of their action. Further investigation and use of such natural compounds could improve preventative and remedial strategies aimed to limit the transmission of campylobacters and other human pathogens via the food chain.

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

Levodopa remains the primary drug for controlling motor symptoms in Parkinson’s disease through the whole course, but over time, complications develop in the form of dyskinesias, which gradually become more frequent and severe. These abnormal, involuntary, hyperkinetic movements are mainly characteristic of the ON phase and are triggered by excess exogenous levodopa. They may also occur during the OFF phase, or in both phases. Over the past 10 years, the issue of levodopa-induced dyskinesia has been the subject of research into both the substrate of this pathology and potential remedial strategies. The purpose of the present study was to review the results of recent research on the background and treatment of dyskinesia. To this end, databases were reviewed using a search strategy that included both relevant keywords related to the topic and appropriate filters to limit results to English language literature published since 2010. Based on the selected papers, the current state of knowledge on the morphological, functional, genetic and clinical features of levodopa-induced dyskinesia, as well as pharmacological, genetic treatment and other therapies such as deep brain stimulation, are described.

An Invitation from the Displaced: Refuge Restaged in The Jungle and As Far as My Fingertips Take Me

Tania El Khoury’s audience-of-one performance piece As Far as My Fingertips Take Me and Joe Murphy and Joe Robertson’s play The Jungle, produced and developed by Good Chance, are twenty-first-century productions that foreground the medial affordances of performance art and drama to foreground Western audiences’ relationships and responses to refugees. I propose a taxonomy of the strategies used in these two works as a model for analyzing theatre and performance about refugees. These strategies are classified in terms of the responses they seek to elicit from the audience, and my analysis explores some of the tactics used to achieve these goals. Remedial strategies counter harmful stereotypes about refugees; transformative strategies challenge and reshape basic conceptions of self, other, nation, and citizenship; and ethotic strategies reorient the audience to consider their relationship with refugees, particularly with respect to their disparate identity positions, mutual responsibility, and interdependence. Fingertips and The Jungle are substantially different artworks but are able to achieve similar results by utilizing the different affordances of their respective mediums. Thus, the taxonomy of strategies provides a more systematic and precise way of analyzing how refugee drama and performance achieve their goals. It avoids being overly prescriptive in how these goals should be achieved and instead recognizes how exploiting different tactics and medial affordances can advocate for refugees and other migrants.

Availability of essential medicines in Pakistan—A comprehensive document analysis

Introduction Access to essential medicines (EMs) is a basic human right. Non-availability and shortages of EMs are reported for Pakistan but there is insufficient data to define the nature and magnitude of this problem. The current study is designed to systematically analyze the medicines included in the National Essential Medicines List (NEML) for their availability through comprehensive document analysis. Methods An expanded list of medicinal items was developed using the NEML of Pakistan (2018) to enlist individual medicines with their specifications. Registration status of the medicines was searched using three publicly accessible information sources; Pharmaguide 25th Edition, 2018–19, the on-line Drug Information System, and the Mobile Application Pharmapedia followed by a later 3-step validation of the data. The unregistered EMs were then further categorized into three subgroups in accordance with their possible remedial strategies. Findings The 19 studied categories comprised 690 EMs and it was found that 179 (26%) of these EMs don not have a registration status. However, it was also identified that the availability of 47 (26.2%) out of 179 unregistered EMs can be enssured by strengthening compounding services, and prioritizing registration of age-appropriate formulations. Availability of another 39 (21.7%) such medicines can be ensured by revising the NEML or the product registrations for the slight differences in their different specifications. The categories showing high proportion of unregistered medicines included anti-Parkinson’s medicines (100%), antidotes and other substances used in poisoning (60%), diuretics (47%), anticonvulsants/antiepileptics (42%), hormones and other endocrine medicines and contraceptives (38%), medicines for mental and behavioral disorders (30%), anti-infectives (27%), medicines for pain and palliative care (26%), medicines for neonatal care (25%), medicines for diseases of joint (25%), gastrointestinal medicines (24%) and cardiovascular medicines (15%). Conclusion The study shows the absence of registration status of a significant number of EMs in Pakistan. This could be major barrier in their access. Strategies are needed to strengthen the processes of their registration on priority basis.

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

Levodopa remains the primary drug for controlling motor symptoms in Parkinson's disease through the whole course, but over time complications develop in the form of dyskinesias, which gradually become more frequent and severe. These abnormal, involuntary, hyperkinetic movements are mostly characteristic of the ON phase and reflect an excess of exogenous levodopa. They may also occur during OFF phase, or in both phases. Over the past 10 years, the issue of levodopa-induced dyskinesia has been the subject of research into both the substrate of this pathology and potential remedial strategies. The purpose of the present study was to review the results of recent research on the background and treatment of dyskinesia. To this end, databases were reviewed using a search strategy that included both relevant keywords related to the topic and appropriate filters to limit results to English-language literature published since 2010. Based on the selected papers, the current state of knowledge on morphological, functional, genetic, and clinical features of levodopa-induced dyskinesia, as well as pharmacological, genetic treatment and other therapies such as deep brain stimulation are described.

Reframing, Remorse, and Reassurance: Remedial Work in Diplomatic Crises

This paper suggests a framework for studying how remedial actions are deployed following diplomatic crisis. On the basis of thirty-four case studies and twenty-one interviews with senior statespersons, we offer a novel typology of remedial strategies employed for diffusing interstate tension and pinpoint the various calculations taken by decision-makers in performing them. The analysis reveals three primary strategies for restoring diplomatic relations, the last of which was neglected thus far in the literature: reframing, wherein state actors negotiate the definition of transgressions and their responsibility for its occurrence; remorse, wherein the accused actors acknowledge ranging degrees of responsibility for committing wrongdoing; and finally, reassurance, wherein actors channel the remedial focus to the future relationship between the involved parties. Moreover, statespersons articulated several considerations taken into account when selecting a specific remedial strategy: the perceived value of the offended party, domestic political criticism, levels of publicity, adjusting a specific remedy to the target audience, and self-image. We conclude by discussing the value of remedial work for the study of diplomatic crises. Cet article suggère un cadre pour l’étude de la manière dont des actions correctives sont déployées suite à une crise diplomatique. Nous nous sommes basés sur trente-quatre études de cas et vingt-et-un entretiens avec des hauts responsables d’État pour proposer une nouvelle typologie des stratégies correctives employées pour atténuer la tension entre États et identifier les divers calculs effectués par les décideurs pour les exécuter. Cette analyse révèle trois principales stratégies de restauration des relations diplomatiques, et la dernière d'entre elles a jusqu'ici été négligée par la littérature: celle du recadrage, dans laquelle les acteurs étatiques négocient la définition des transgressions et leur responsabilité dans leur manifestation; celle du remords, dans laquelle les acteurs accusés admettent leurs divers degrés de responsabilité dans l'engagement dans une mauvaise conduite; et enfin, celle de la réassurance, dans laquelle les acteurs canalisent leur attention corrective sur la future relation entre les parties impliquées. De plus, les responsables d’État ont articulé plusieurs considérations prises en compte lors de la sélection d'une stratégie corrective spécifique: la valeur perçue de la partie offensée, la critique politique intérieure, les niveaux de publicité, l'adaptation d'une action corrective spécifique au public cible et l'image de soi. Nous concluons par une discussion sur la valeur du travail correctif pour l’étude des crises diplomatiques. Este artículo sugiere un marco para estudiar cómo se implementan las acciones correctivas tras una crisis diplomática. Sobre la base de treinta y cuatro estudios de casos y veintiuna entrevistas con altos cargos del estado, ofrecemos una novedosa tipología de las estrategias correctivas empleadas para rebajar las tensiones interestatales y señalamos los distintos cálculos realizados por los responsables al llevarlas a cabo. El análisis revela tres estrategias principales para el restablecimiento de las relaciones diplomáticas, esta última se no se había tenido en cuenta hasta ahora en la bibliografía: el replantamiento, en el que los actores estatales negocian la definición de las transgresiones y su responsabilidad; el remordimiento, en el que los actores acusados reconocen distintos grados de responsabilidad por cometer delitos; y, por último, la reafirmación, en la que los actores canalizan el enfoque correctivo hacia la futura relación entre las partes implicadas. Además, los cargos del estado expresaron varias consideraciones que se tienen en cuenta a la hora de seleccionar una estrategia correctiva específica: el valor percibido por la parte ofendida, la crítica política interna, los niveles de publicidad, el ajuste de las acciones correctivas específicas al público y la imagen propia. Concluimos con el análisis del valor del trabajo correctivo para el estudio de las crisis diplomáticas.