Closing the Gap between Experiment and Simulation─A Holistic Study on the Complexation of Small Interfering RNAs with Polyethylenimine.

Rational design is pivotal in the modern development of nucleic acid nanocarrier systems. With the rising prominence of polymeric materials as alternatives to lipid-based carriers, understanding their structure-function relationships becomes paramount. Here, we introduce a newly developed coarse-grained model of polyethylenimine (PEI) based on the Martini 3 force field. This model facilitates molecular dynamics simulations of true-sized PEI molecules, exemplified by molecules with molecular weights of 1.3, 5, 10, and 25 kDa, with degrees of branching between 50.0 and 61.5%. We employed this model to investigate the thermodynamics of small interfering RNA (siRNA) complexation with PEI. Our simulations underscore the pivotal role of electrostatic interactions in the complexation process. Thermodynamic analyses revealed a stronger binding affinity with increased protonation, notably in acidic (endosomal) pH, compared to neutral conditions. Furthermore, the molecular weight of PEI was found to be a critical determinant of binding dynamics: smaller PEI molecules closely enveloped the siRNA, whereas larger ones extended outward, facilitating the formation of complexes with multiple RNA molecules. Experimental validations, encompassing isothermal titration calorimetry and single-molecule fluorescence spectroscopy, aligned well with our computational predictions. Our findings not only validate the fidelity of our PEI model but also accentuate the importance of in silico data in the rational design of polymeric drug carriers. The synergy between computational predictions and experimental validations, as showcased here, signals a refined and precise approach to drug carrier design.

Optimizing ß-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer.

AIMS: The current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic-pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV. METHODS: In vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration vs. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC. RESULTS: A weight-banded dosing regimen including 150-600 mg rifampicin once daily, 250-1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily. CONCLUSION: The higher PTA values support the proposed 4-drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.

Dose rationale for the use of meropenem/vaborbactam combination in paediatric patients with Gram-negative bacterial infections.

AIMS: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients. METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months). CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).

Multi-target rational design and synthesis of novel diphenyl-tethered pyrazolopyrimidines targeting EGFR and topoisomerase II with potential DNA intercalation and apoptosis induction.

Herein, we envisioned the design and synthesis of novel pyrazolopyrimidines (confirmed by elemental analysis, 1H and 13C NMR, and mass spectra) as multitarget-directed drug candidates acting as EGFR/TOPO II inhibitors, DNA intercalators, and apoptosis inducers. The target diphenyl-tethered pyrazolopyrimidines were synthesized starting from the reaction of phenyl hydrazine and ethoxymethylenemalononitrile to give aminopyrazole-carbonitrile 2. The latter hydrolysis with NaOH and subsequent reaction with 4-chlorobenzaldhyde afforded the corresponding pyrazolo[3,4-d]pyrimidin-4-ol 4. Chlorination of 4 with POCl3 and sequential reaction with different amines afforded the target compounds in good yields (up to 73 %). The growth inhibition % of the new derivatives (6a-m) was investigated against different cancer and normal cells and the IC50 values of the most promising candidates were estimated for HNO97, MDA-MB-468, FaDu, and HeLa cancer cells. The frontier derivatives (6a, 6i, 6k, 6l, and 6m) were pursued for their EGFR inhibitory activity. Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib as a reference standard. On the other side, compounds (6a, 6i, 6k, 6l, and 6m) underwent topoisomerase II (TOPO II) inhibitory assay. In particular, compounds 6a and 6l exhibited IC50s of 17.89 and 19.39 µM, respectively, surpassing etoposide with IC50 of 20.82 µM. Besides, the DNA fragmentation images described the great potential of both candidates 6a and 6l in inducing DNA degradation at lower concentrations compared to etoposide and doxorubicin. Moreover, compound 6l, with the most promising EGFR/TOPO II inhibition and DNA intercalation, was selected for further investigation for its apoptosis induction ability by measuring caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 proteins. Additionally, molecular docking was used to explain the SAR results based on the differences in the molecular features of the investigated congeners and the target receptors' topology.

Pharmacophore-based, rationale design, and efficient synthesis of novel tetrahydrobenzo[b]thiophene candidates as potential dual Topo I/II inhibitors and DNA intercalators.

A series of tetrahydrobenzo[b]thiophene derivatives was designed and synthesized as dual topoisomerase (Topo) I/II inhibitors implicating potential DNA intercalation. Ethyl-2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylate (1) was prepared by modification of the Gewald reaction procedure using a Fe2O3 nanocatalyst and then it was used as a building block for the synthesis of tetrahydrobenzo[b]thiophene candidates (2-14). Interestingly, compound 14 showed the best cytotoxic potential against hepatocellular, colorectal, and breast cancer cell lines (IC50 = 7.79, 8.10, and 3.53 µM), respectively, surpassing doxorubicin at breast cancer (IC50 = 4.17 µM). Meanwhile, the Topo I and II inhibition assay displayed that compound 3 could exhibit the best inhibitory potential among the investigated candidates (IC50 = 25.26 and 10.01 nM), respectively, in comparison to camptothecin (IC50 = 28.34 nM) and doxorubicin (IC50 = 11.01 nM), as reference standards. In addition, the DNA intercalation assay showed that compound 14 could display the best binding affinity with an IC50 value of 77.82 µM in comparison to doxorubicin (IC50 = 58.03 µM). Furthermore, cell cycle and apoptosis analyses described that compound 3 prompts the G1 phase arrest in michigan cancer foundation-7 cancer cells and increases the apoptosis ratio by 29.31% with respect to untreated cells (2.25%). Additionally, the conducted molecular docking assured the promising binding of the investigated members toward Topo I and II with potential DNA intercalation. Accordingly, the synthesized compounds could be treated as promising anticancer candidates for future optimization.

Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

What are economic costs and when should they be used in health economic studies?

Economic analyses of healthcare interventions are an important consideration in evidence-based policymaking. A key component of such analyses is the costs of interventions, for which most are familiar with using budgets and expenditures. However, economic theory states that the true value of a good/service is the value of the next best alternative forgone as a result of using the resource and therefore observed prices or charges do not necessarily reflect the true economic value of resources. To address this, economic costs are a fundamental concept within (health) economics. Crucially, they are intended to reflect the resources' opportunity costs (the forgone opportunity to use those resources for another purpose) and they are based on the value of the resource's next-best alternative use that has been forgone. This is a broader conceptualization of a resource's value than its financial cost and recognizes that resources can have a value that may not be fully captured by their market price and that by using a resource it makes it unavailable for productive use elsewhere. Importantly, economic costs are preferred over financial costs for any health economic analyses aimed at informing decisions regarding the optimum allocation of the limited/competing resources available for healthcare (such as health economic evaluations), and they are also important when considering the replicability and sustainability of healthcare interventions. However, despite this, economic costs and the reasons why they are used is an area that can be misunderstood by professionals without an economic background. In this paper, we outline to a broader audience the principles behind economic costs and when and why they should be used within health economic analyses. We highlight that the difference between financial and economic costs and what adjustments are needed within cost calculations will be influenced by the context of the study, the perspective, and the objective.

Assessment of the capacity of ChatGPT as a self-learning tool in medical pharmacology: a study using MCQs.

BACKGROUND: ChatGPT is a large language model developed by OpenAI that exhibits a remarkable ability to simulate human speech. This investigation attempts to evaluate the potential of ChatGPT as a standalone self-learning tool, with specific attention on its efficacy in answering multiple-choice questions (MCQs) and providing credible rationale for its responses. METHODS: The study used 78 test items from the Korean Comprehensive Basic Medical Sciences Examination (K-CBMSE) for years 2019 to 2021. 78 test items translated from Korean to English with four lead-in prompts per item resulted in a total of 312 MCQs. The MCQs were submitted to ChatGPT and the responses were analyzed for correctness, consistency, and relevance. RESULTS: ChatGPT responded with an overall accuracy of 76.0%. Compared to its performance on recall and interpretation questions, the model performed poorly on problem-solving questions. ChatGPT offered correct rationales for 77.8% (182/234) of the responses, with errors primarily arising from faulty information and flawed reasoning. In terms of references, ChatGPT provided incorrect citations for 69.7% (191/274) of the responses. While the veracity of reference paragraphs could not be ascertained, 77.0% (47/61) were deemed pertinent and accurate with respect to the answer key. CONCLUSION: The current version of ChatGPT has limitations in accurately answering MCQs and generating correct and relevant rationales, particularly when it comes to referencing. To avoid possible threats such as spreading inaccuracies and decreasing critical thinking skills, ChatGPT should be used with supervision.

The rationale for treating uveal melanoma with adjuvant melatonin: a review of the literature.

BACKGROUND: Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. METHODS: Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. RESULTS: Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. CONCLUSIONS: Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Increasing Acceptability and Outcome Expectancy for Internet-Based Cognitive Behavioral Therapy During the COVID-19 Pandemic.

Background:e-Health interventions for mental health have the potential to reduce burdens on health care systems, but large survey studies find low acceptability for these interventions. The COVID-19 pandemic may make attitudes toward e-health more malleable. The current study examined whether an intervention to improve attitudes toward Internet-based cognitive behavioral therapy (iCBT) has a greater impact during the COVID-19 pandemic than before the pandemic.Materials and Methods:Individuals (N = 662) recruited from a large university and surrounding community who participated in a study about the acceptability of iCBT in 2018 and 2019 were asked to participate in a follow-up survey. In the original study, participants were randomized to receive or not receive a rationale designed to increase acceptability of iCBT, and then they completed measures of acceptability and outcome expectancy for iCBT. Fifty-one participants enrolled in the follow-up study from May to July 2020. They received a treatment rationale for iCBT (or not) in keeping with randomization from the parent study and re-completed measures assessing the acceptability and outcome expectancy for iCBT.Results:Contrary to hypotheses, two-way analyses of covariance (ANCOVA's) demonstrated that there was no significant interaction between time point and rationale condition on acceptability or outcome expectancy for iCBT. There was a significant main effect of rationale condition on acceptability, such that participants who received a treatment rationale reported greater acceptability for iCBT. There were no significant main effects of time.Conclusions:A treatment rationale was effective in improving acceptability for iCBT in a general population sample, but not more so during the COVID-19 pandemic.

Turkish Version of the Interpretation of Death Scale: Cultural Adaptation and Validation.

This study aimed to adapt and validate the Interpretation of Death Scale (IOD) in the sociocultural context of Turkey. Three samples participated in this study (n1 = 280, n2 = 254 and n3 = 45 individuals). Principal component analysis with a promax rotation showed 14 items and three factors which explained 54.33% of the total variability. Confirmatory factor analysis indicated acceptable fits. Significant correlations were found between IOD and mortality awareness and meaning in life. The reliability coefficients were also found acceptable. It can be concluded that IOD is a promising instrument in assessing the interpretation of death scores in Turkey.

Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Evaluation of pharmacokinetic-pharmacodynamic relationships and selection of drug combinations for tuberculosis.

AIMS: Despite evidence of the efficacy of anti-tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for combination therapy remains empirical. Novel methods are needed to optimise the antibacterial activity in combination therapies. A drug-disease modelling framework for rational selection of dose and drug combinations in tuberculosis is presented here. METHODS: A model-based meta-analysis was performed to assess the antibacterial activity of different combinations in infected mice. Data retrieved from the published literature were analysed using a two-state bacterial growth dynamics model, including fast- and slow-growing bacterial populations. The contribution of each drug to the overall antibacterial activity of the combination was parameterised as relative change to the potency of the backbone drug (EC50 -F and/or EC50 -S). Rifampicin and bedaquiline were selected as paradigm drugs to evaluate the predictive performance of the modelling approach. RESULTS: Pyrazinamide increased the potency (EC50 -F and EC50 -S) of rifampicin (RZ) and bedaquiline (BZ) by almost two-fold. By contrast, pretomanid and isoniazid were found to worsen the antibacterial activity of BZ and RZ, respectively. Following extrapolation of in vivo pharmacokinetic-pharmacodynamic relationships, the dose of rifampicin showing maximum bactericidal effect in tuberculosis patients was predicted to be 70 mg·kg-1 when given in combination with pyrazinamide. CONCLUSIONS: The use of a drug-disease modelling framework may provide a more robust rationale for extrapolation and selection of dose and companion drugs in humans. Our analysis demonstrates that RZ and BZ should be considered as a backbone therapy in prospective novel combination regimens against tuberculosis.

Extrapolation and dosing recommendations for raxibacumab in children from birth to age <18 years.

AIMS: The US Food and Drug Administration's Animal Rule allows for the approval of drugs when human efficacy studies are not ethical. While the therapeutic doses of raxibacumab, a monoclonal antibody for the prophylaxis and treatment of inhalational anthrax, have been based on pharmacokinetic data from adult subjects, its disposition in children has not been investigated in clinical trials. Here we evaluate the effect of demographic covariates and maturation processes on the pharmacokinetics of raxibacumab and explore opportunities for the optimisation of paediatric doses. METHODS: A population pharmacokinetic model was used as basis for the extrapolation of raxibacumab disposition from adults to children. Different extrapolation scenarios, including weight-banded dosing regimens, were considered to assess the effect of growth and maturation on the pharmacokinetic parameters of interest. Area under the concentration-time curve, maximum plasma concentration and the time of serum raxibacumab concentrations greater than or equimolar to the highest serum protective antigen concentrations observed for at least 28 days in any monkey challenged with Bacillus anthracis that died were derived and compared with the currently approved US doses. RESULTS: Based on practical considerations, a weight-banded dosing regimen consisting of 4 dose levels (75 mg/kg for individuals ≤1.5 kg, 55 mg/kg for individuals <10 kg, 45 mg/kg for individuals <50 kg, 40 mg/kg for all individuals >50 kg) was required to optimise target exposure across the paediatric population. CONCLUSIONS: Age-related maturation processes may affect raxibacumab clearance in very young patients. The proposed dosing regimens take into account effects of body weight and maturation processes on the elimination of raxibacumab.

Alcohol-related Behavioral Research and its Integration into Primary and Secondary HIV Preventive Interventions: Introduction.

The purpose of this paper is to provide a brief introduction to and description of the contents of this special issue of AIDS and Behavior. The article begins with a description of the rationale for the special issue and the origin of its compilation. This background information is followed by a brief description of the main articles that are included in the special issue, which is structured by Gaist and Stirrat's [4] definitions of types of behavioral and social science research for HIV-AIDS research. The "bookend" article to this introduction is by Robert Freeman and identifies future directions for research and clinical practice that the special issue articles' content suggests.

Homogeneity of cognitive and behavioural processes underlying the relationship between insomnia and body image disturbance.

Specific cognitive behavioural mechanisms related to selective attention, situational avoidance and physical appearance are implicated in the development and maintenance of insomnia and negative reinforcement of body image disturbances. Therefore, we examined whether these processes potentially mediate the relationship between insomnia and body image perception. N = 728 participants completed self-reported measures of sleep-associated monitoring, insomnia symptoms, body image disturbance and coping with body image challenges. Symptoms of insomnia and sleep-associated monitoring behaviour were independently related to increased reports of body image disturbance, cognitive distortions of body image, appearance fixing (i.e. altering appearance by covering, camouflaging or correcting the perceived defect), avoidance (i.e. attempt to escape or avert stressful body image situations) and reduced levels of positive rationale acceptance (i.e. acceptance of the challenging event and positive self-care or rationale self-talk about one's appearance). More crucially, sleep-related monitoring on awakening, cognitive distortion of body image and negative coping strategies related to body image (i.e. appearance fixing, avoidance, rationale acceptance) mediated the relationship between reports of body image disturbance and insomnia symptoms. The current findings expand upon previous research demonstrating consistent relationships between poor sleep and increased dissatisfaction with cutaneous features, by providing novel evidence that body image disturbances are associated with symptoms of insomnia. More crucially, we highlight the role of particular cognitive and behavioural mechanisms pertaining to sleep (i.e. selective attention for physical signs of poor sleep) and body image (i.e. avoidance and rationale acceptance) which may be targeted as part of cognitive behavioural treatments.

Brain Death as the End of a Human Organism as a Self-moving Whole.

The biophilosophic justification for the idea that "brain death" (or total brain failure) is death needs to support two claims: (1) that what dies in human death is a human organism, not merely a psychological entity distinct from it; (2) that total brain failure signifies the end of the human organism as a whole. Defenders of brain death typically assume without argument that the first claim is true and argue for the second by defending the "integrative unity" rationale. Yet the integrative unity rationale has fallen on hard times. In this article, I give reasons for why we should think of ourselves as organisms, and why the "fundamental work" rationale put forward by the 2008 President's Council is better than the integrative unity rationale, despite persistent objections to it.

Activity-Centred Analysis and Design (ACAD): Core purposes, distinctive qualities and current developments.

This paper provides a summary account of Activity-Centred Analysis and Design (ACAD). ACAD offers a practical approach to analysing complex learning situations, in a way that can generate knowledge that is reusable in subsequent (re)design work. ACAD has been developed over the last two decades. It has been tested and refined through collaborative analyses of a large number of complex learning situations and through research studies involving experienced and inexperienced design teams. The paper offers a definition and high level description of ACAD and goes on to explain the underlying motivation. The paper also provides an overview of two current areas of development in ACAD: the creation of explicit design rationales and the ACAD toolkit for collaborative design meetings. As well as providing some ideas that can help teachers, design teams and others discuss and agree on their working methods, ACAD has implications for some broader issues in educational technology research and development. It questions some deep assumptions about the framing of research and design thinking, in the hope that fresh ideas may be useful to people involved in leadership and advocacy roles in the field.

Possibilities and priorities for IJED in times of uncertainty: A 40th anniversary analysis.

This article reflects upon the history of the Journal, its evolving nature and rationale and upon possibilities and priorities for the future in what are uncertain times for all.