There exists consensus that the traditional means by which safety of chemicals is assessed-namely through reliance upon apical outcomes obtained following in vivo testing-is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of "new approach methodologies" (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged. It has been suggested, intuitively, that combining data obtained from across these sources might serve to enhance overall confidence in derived judgment. This concept may be formalised in the "tiered assessment" approach, whereby evidence gathered through a sequential NAM testing strategy is exploited so to infer the properties of a compound of interest. Our intention has been to provide an illustration of how such a scheme might be developed and applied within a practical setting-adopting for this purpose the endpoint of rat acute oral lethality. Bayesian statistical inference is drawn upon to enable quantification of degree of confidence that a substance might ultimately belong to one of five LD50-associated toxicity categories. Informing this is evidence acquired both from existing in silico and in vitro resources, alongside a purposely-constructed random forest model and structural alert set. Results indicate that the combination of in silico methodologies provides moderately conservative estimations of hazard, conducive for application in safety assessment, and for which levels of certainty are defined. Accordingly, scope for potential extension of approach to further toxicological endpoints is demonstrated.

Introduction: Numerous potentially controlling demographic factors such as age, poverty, obesity, and car- diovascular and respiratory co-morbidities have been suggested, and high vitamin D levels have been found, to be associated with lower levels of COVID-19 infection. This study aimed to explore the correlation between vitamin D levels and socio-demographic characteristics with COVID-19 cases and deaths in 20 European countries. Methods: A quantitative ecological study was designed. Multiple linear regression analysis was used to examine which of vitamin D levels and 20 demographic factors correlated well with COVID-19 cases and deaths up to 9 May 2020 in 20 European countries. Data distributions were normalised by the Box and Cox approach and the Minitab routine ‘Best Subsets’ was used to select the best descriptor sets for each quantitative model of cases and deaths. Results: Cases were best modelled by vitamin D levels, stroke deaths, respiratory deaths, smoking, and human development levels. Deaths were best modelled by the number of cases, stroke deaths, proportion of African/Afro-Caribbean people, proportion of over 65-year-olds, population density, and levels of physical inactivity. Good correlations were obtained for each model, with coefficients of determination (r2) being around 0.7 or greater. The correlation of cases with vitamin D levels, stroke deaths, and respiratory deaths was r2 = 0.712, while the correlation of deaths with population density, levels of physical inactivity, and stroke deaths was r2 = 0.745. Discussion and Conclusions: These results help to explain the variability of COVID-19 cases and deaths, and offer guidance in planning against future coronavirus pandemics. Controlling for a wide range of factors reduces the risk that the apparent protective effect of vitamin D might be confounded.

1, 1, 2-Trichloroethylene (TCE) is of environmental concern, due to evaporation while handling, chemical processing and leakage from chemical waste sites, leading to its contamination of ground water and air. For several decades there has been issues about possible long term health effects of TCE but recently the International Agency for Research on Cancer (IARC) and the US Environmental Protection Agency classified TCE as a human carcinogen. Links having been established between occupational exposures and kidney cancer and possible links to non-Hodgkin lymphoma and liver cancer, but there is more still more to learn. In male rats, TCE produces a small increase in the incidence of renal tubule tumours but not in female rats or mice of either sex. However, chronic renal injury was seen in these bioassays in both sexes of rats and mice. The mechanism of kidney injury from TCE is thought to be due to reductive metabolism forming a cysteine conjugate that is converted to a reactive metabolite via the enzyme cysteine conjugate β-lyase. However, TCE also produces a marked and sustained formic aciduria in male rats and it has been suggested that long term exposure to formic acid could lead to renal tubule injury and regeneration. In this study we have determined if TCE produces formic aciduria in male mice following a single and repeat dosing. Male C57 Bl/6OlaHsd mice were dosed with 1000mg/kg by ip injection and urine collected overnight 24, 48, 72 and 96h after dosing. Formic acid was present in urine 24h after dosing, peaked around 48h at 8mg formic acid excreted/mouse, and remained constant over the next 24h and was not back to normal 96h after dosing. This was associated with a marked acidification of the urine. Plasma creatinine and renal pathology was normal. Plasma kinetics of formic acid showed it was readily cleared with an initial half-life of 2.42h followed by a slower rate with a half-life of 239h. Male mice were then dosed twice/week at 1000mg/kg TCE for 56days, as anticipated there was a marked and sustained formic aciduria over the duration of the study. This was associated with acidification of the urine, mild diuresis and a marked fall in urinary ammonia. Six biomarkers of renal injury KIM-1, NGAL, NAG, Cystatin-c, Albumin and IL-18 were measured in urine over time and they all showed a small increase at the later time points indicative of early markers of renal injury. However, there was no histological evidence of renal damage or renal tubule cell proliferation after 8 weeks' exposure to TCE. The concentration of formic acid in plasma at the end of the study was 1.05±0.61mM compared to control, 0.39±0.17mM. In the liver, formic acid was present at a concentration of 1mM in both control and treated mice while in the kidney it was higher at 2mM in both treated and controls. We also report that trichloroacetic acid (TCA) a metabolite of TCE also causes formic aciduria, at doses likely to arise in vivo after 1000mg/kg TCE namely 16 and 32mg/kg. Urinary formic acid peaked 24h after dosing at 4mg formic acid excreted/mouse. Thus, as in male and female rats (Yaqoob et al., 2013) male mice show a marked formic aciduria following TCE which after 8 weeks' exposure did not produce renal injury, but the small rise in renal biomarkers suggest renal damage may occur following longer exposure. Thus, TCE-induced formic aciduria may be a contributor factor in the chronic renal injury seen in male and female rats and mice.

With the introduction of the REACH legislation in the European Union, there is a requirement for property and toxicity data on chemicals produced in or imported into the EU at levels of 1 tonne/year or more. This has meant an increase in the in silico prediction of such data. One of the chief predictive approaches is QSAR (quantitative structure-activity relationships), which is widely used in many fields.A QSAR approach that is increasingly being used is that of artificial neural networks (ANNs), and this chapter discusses its application to the range of physicochemical properties and toxicities required by REACH. ANNs generally outperform the main QSAR approach of multiple linear regression (MLR), although other approaches such as support vector machines sometimes outperform ANNs. Most ANN QSARs reported to date comply with only two of the five OECD Guidelines for the Validation of (Q)SARs.

This chapter introduces the use of one-sided tests where an experiment was designed to find out whether an endpoint changes in a specified direction. One-sided testing can be used to test for changes in one specified direction. It describes the special form of null hypothesis used in one-sided tests and the use of one-sided confidence intervals to test such null hypotheses. The chapter shows that, in marginal cases, data may be nonsignificant when assessed by a two-sided test, and yet be significant with the one-sided version of the same test. It reviews the age old trick of switching from a two-sided to a one-sided test thereby converting disappointing nonsignificance to the much coveted significance. The chapter shows that said trick is not acceptable because it raises the risk of a false positive to 10% instead of the standard 5% and sets out the correct protocol for using one-sided tests.

This chapter describes the difference between paired and unpaired data and it demonstrates that the paired t-test has greater power than the two-sample t-test when dealing with paired data. The paired t-test is used where data form natural pairs. Its classic use arises when we've observed the same individual under two different circumstances. The paired t-test offers the greatest advantage over the two-sample t-test when values are much higher in some individuals than in others, but all individuals show roughly the same change. It explains the source of its superior power and show how the paired t-test is performed. The chapter explores the merits of paired versus unpaired experimental designs. General statistical methods such as sample size estimation, determination of practical significance and one-sided testing can be applied to the paired t-test in the same manner that we have already seen for the two-sample t-test.

Electronic marking tools that incorporate statement banks have become increasingly prevalent within higher education. In an experiment, printed and emailed feedback was returned to 243 first-year students on a credit-bearing laboratory report assessment. A transmission approach was used, students being provided with comments on their work, but no guidance as to how they should use these remarks. A multiple-choice question test, undertaken before and after the return of feedback, was used to measure learning. Although returned comments included model answers, test scores showed no overall enhancement, even when students' marks for their laboratory reports were initially hidden. A negative and significant (p=.010) linear trend between relative test scores and test date suggests that even modest improvements in subject knowledge were lost over time. Despite this, students could accurately guess their mark based on emailed feedback alone, estimated and awarded marks being linearly correlated (p<.001). It is concluded that statement banks organised according to published assessment criteria can ultimately help students to appreciate how their work was graded. However, students should be encouraged to produce a structured response to received feedback if self-assessment is to occur.

AIMS AND OBJECTIVES:This study used a 'Lean' technique, the 'waste walk' to evaluate the activities of clinical pharmacists with reference to the seven wastes described in 'Lean' including 'defects', 'unnecessary motion', 'overproduction', 'transport of products or material', 'unnecessary waiting', 'unnecessary inventory' and 'inappropriate processing'. The objectives of the study were to categorise the activities of ward-based clinical pharmacists into waste and non-waste, provide detail around what constitutes waste activity and quantify the proportion of time attributed to each category.SETTING:This study was carried out in a district general hospital in the North West of England.METHOD:Staff were observed using work-sampling techniques, to categorise activity into waste and non-waste, with waste activities being allocated to each of the seven wastes described earlier and subdivided into recurrent themes.KEY FINDINGS:Twenty different pharmacists were observed for 1 h on two separate occasions. Of 1440 observations, 342 (23.8%) were categorised as waste with 'defects' and 'unnecessary motion' accounting for the largest proportions of waste activity.CONCLUSION:Observation of clinical pharmacists' activities has identified that a significant proportion of their time could be categorised as 'waste'. There are practical steps that could be implemented in order to ensure their time is used as productively as possible. Given the challenges facing the UK National Health Service, the adoption of 'Lean' techniques provides an opportunity to improve quality and productivity while reducing costs.

Polypharmacy is increasing, seemingly inexorably, and inevitably the associated difficulties for individual patients of coping with multiple medicines rise with it. Using medicines is one aspect of the burden associated with living with a chronic condition. It is becoming increasingly important to measure this burden particularly that relating to multiple long-term medicines. Pharmacists and other health professionals provide a myriad of services designed to optimise medicines use, ostensibly aiming to help and support patients, but in reality many such services focus on the medicines, and seek to improve adherence rather than reducing the burden for the patient. We believe that the patient perspective and experience of medicines use is fundamental to medicines optimisation and have developed an instrument which begins to quantify these experiences. The instrument, the Living with Medicines Questionnaire, was generated using qualitative findings with patients, to reflect their perspective. Further development is ongoing, involving researchers in multiple countries.

Background Polypharmacy is increasing and managing large number of medicines may create a burden for patients. Many patients have negative views of medicines and their use can adversely affect quality of life. No studies have specifically explored the impact of general long-term medicines use on quality of life. Objective To determine the issues which patients taking long-term medicines consider affect their day-to-day lives, including quality of life. Setting Four primary care general practices in North West England Methods Face-to-face interviews with adults living at home, prescribed four or more regular medicines for at least 1 year. Interviewees were identified from primary care medical records and purposively selected to ensure different types of medicines use. Interviews were recorded, transcribed and analysed thematically. Results Twenty-one interviews were conducted and analysed. Patients used an average of 7.8 medicines, 51 % were preventive, 40 % for symptom relief and 9 % treatment. Eight themes emerged: relationships with health professionals, practicalities, information, efficacy, side effects, attitudes, impact and control. Ability to discuss medicines with health professionals varied and many views were coloured by negative experiences, mainly with doctors. All interviewees had developed routines for using multiple medicines, some requiring considerable effort. Few felt able to exert control over medicines routines specified by health professionals. Over half sought additional information about medicines whereas others avoided this, trusting in doctors to guide their medicines use. Patients recognised their inability to assess efficacy for many medicines, notably those used for prophylaxis. All were concerned about possible side effects and some had poor experiences of discussing concerns with doctors. Medicines led to restrictions on social activities and personal life to the extent that, for some, life can revolve around medicines. Conclusion There is a multiplicity and complexity of issues surrounding medicines use, which impact on day-to-day lives for patients with long-term conditions. While most patients adapt to long-term medicines use, others did so at some cost to their quality of life.

Hydrophobicity is an intrinsic property that relates to a chemical's tendency to partition between a polar and a nonpolar phase. Traditionally, hydrophobicity has been described by the logarithm of the octanol-water partition coefficient (log K-OW or log P). Immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC) is an alternative method to determine hydrophobicity that may be more biologically relevant. This paper examines the robustness of an IAM-HPLC assay optimized using the IAM.PC.DD2 column to determine the retention factor (log k(IAM) ((pH 7.4))). The method has been shown to be robust following robustness testing of five compounds (log K-OW ranging from 0.29 to 6.03) assessed across five columns (which included three batches of stationary phase) and two HPLC systems.

Background: Causality assessment is used to determine the likelihood that a drug caused a particular adverse event. There are multiple methods for assessing the causality of suspected adverse drug reactions (ADRs). Undertaking some form of causality assessment of suspected ADRs is part of pharmacovigilance practice, but potentially without value if reproducibility of the results is consistently poor, and may vary with the background and experience of the assessor.

International Journal of Pharmacy PracticeVolume 18, Issue 2 p. 125-127 Outcome measures: a sensitive approach Janet Krska, Janet Krska School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UKSearch for more papers by this authorPhilip H. Rowe, Philip H. Rowe School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UKSearch for more papers by this author Janet Krska, Janet Krska School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UKSearch for more papers by this authorPhilip H. Rowe, Philip H. Rowe School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UKSearch for more papers by this author First published: 30 March 2010 https://doi.org/10.1211/ijpp.18.02.0009 Correspondence: Professor Janet Krska, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. E-mail: j.krska@ljmu.ac.uk Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume18, Issue2April 2010Pages 125-127 RelatedInformation

AIM The proportion of re-admissions to hospital caused by ADRs is poorly documented in the UK. The aim of this study was to evaluate the impact of ADRs on re-admission to hospital after a period as an inpatient. METHODS One thousand patients consecutively admitted to 12 wards were included. All subsequent admissions for this cohort within 1 year of discharge from the index admission were retrospectively reviewed. RESULTS Of the 1000 patients included, 403 (40.3%, 95% CI 39.1, 45.4%) were re-admitted within 1 year. Complete data were available for 290 (70.2%) re-admitted patients, with an ADR contributing to admission in 60 (20.8%, 95% CI 16.4, 25.6%) patients. Presence of an ADR in the index admission did not predict for an ADR-related re-admission (10.5% vs. 7.2%, P=0.25), or re-admission overall (47.2% vs. 41.2%, P=0.15). The implicated drug was commenced in the index admission in 33/148 (22.3%) instances, with 37/148 (25%) commenced elsewhere since the index admission. Increasing age and an index admission in a medical ward were associated with a higher incidence of re-admission ADR. The most frequent causative drugs were anti-platelets and loop diuretics, with bleeding and renal impairment the most frequent ADRs. Over half (52/91, 57.1%) of the ADRs were judged to be definitely or possibly avoidable. CONCLUSIONS One fifth of patients re-admitted to hospital within 1 year of discharge from their index admission are re-admitted due to an ADR. Our data highlight drug and patient groups where interventions are needed to reduce the incidence of ADRs leading to re-admission.

Objectives This study assessed the impact of the introduction of medicines vending units (MVUs) into an Emergency Department (ED) on nursing time spent on medicines-use processes. The objectives included identification of changes in nursing activities pre- and post-automation and the impact of automation on the time needed for nurses to access medicines and replenish ward stock. Methods This study was carried out in a district general hospital ED which is attended by over 65 000 patients each year. Staff were observed using work sampling techniques to compare activity before and after the introduction of MVUs. To assess possible changes in dose acquisition time, staff were timed withdrawing doses of medicines from traditional storage units and then from MVUs. To obtain baseline data about traditional methods of replenishing stock, nursing staff recorded the time at which traditional stock replenishment was carried out and the time required to do it. Key findings Nursing staff spent approximately 11% of their time on work activities related to medicines pre-automation and 12% post-automation (P = 0.234). The median time to acquire a dose of medication decreased from 139.5 s pre-automation to 44 s post-automation (P < 0.0001). Following automation, a total of 7.1 h/day could be saved in nursing time. A mean saving of 46.5 min/week was also identified because nursing staff are no longer involved in stock replenishment. Conclusions A significant release of nursing time was identified from the observed acquisition of doses of medicines from the MVU. Work sampling techniques suggest this does not appear to have translated into significant savings on nursing time dealing with medicines, although the nature of these activities has changed.

The national movement towards progress files, incorporating personal development planning and reflective learning, is supported by lecturers providing effective feedback to their students. Recent technological advances mean that higher education tutors are no longer obliged to return comments in the 'traditional' manner, by annotating students' work with red pen. This paper considers some of the options currently available for returning computer-assisted feedback, including the Electronic Feedback freeware. This MS Office application enables tutors to readily synthesise and email feedback reports to students. To further ascertain the value of this software, 169 1st-year Pharmaceutical Science and Pharmacy students completed a questionnaire to gauge their reaction to formative feedback on an extended laboratory report. This included 110 responses from students graded by three tutors who marked work using either handwritten annotations or the Electronic Feedback program. Principle component analysis (PCA) of the Likert scale responses indicates that the identity of the marker did not significantly affect the response of students. However, the type of feedback was a factor that influenced the students' responses, with electronic feedback being rated superior. A Mann-Whitney analysis of the satisfaction ratings (generated by PCA) indicates that four features of the assignment and feedback were considered significantly improved when the software was used to create feedback, namely; markscheme clarity, feedback legibility, information on deficient aspects, and identification of those parts of the work where the student did well. Modern academics face a number of challenges if they wish to return meaningful and timely feedback to students, among them large class sizes and infrequent face-to-face contact. It is pleasing to note, therefore, that assessors reported taking less time to mark when using the software. It is concluded that electronic formative feedback can be returned more quickly and may be used to synthesise relevant feedback that is both fair and balanced.

This study has assessed the use of consensus regression, as compared to single multiple linear regression, models for the development of quantitative structure-activity relationships (QSARs). To provide a comparison, four data sets of varying size and complexity were analyzed: silastic membrane flux, toxicity of phenols to Tetrahymena pyriformis, acute toxicity to the fathead minnow and flash point. For each data set, a genetic algorithm was used to develop a model population and the performance of consensus models was compared to that of the best single model. Two consensus models were developed, one using the top 10 models, and the other using a subset of models chosen to provide maximal coverage of model space. The results highlight the ability of the genetic algorithm to develop predictive models from a large descriptor pool. However, the consensus models were shown to offer no significant improvements over single regression models, which are as statistically robust as the equivalent consensus models. Consensus models developed from a selection of the best QSARs were shown not to be superior to a selection of diverse in "model space" QSARs. For the data sets analyzed in this study, and in light of the Organization for Economic Cooperation and Development principles for the validation of QSARs, the increase in model complexity when using consensus models does not seem warranted given the minimal improvement in model statistics.

The aim of this study was to evaluate the effectiveness of a system for the allocation of students to final year projects and to assess the equality of marking between projects undertaken within different research disciplines. Comparison of mean project marks were assessed by analysis of variance, using analysis of covariance to take into account student academic ability based on their overall third year mark. Results showed that each research discipline was being allocated students with a similar cross-section of ability, with no statistically significant variance in either cohort. Comparing mean project marks between specific research groups, corrected by year-three performance, revealed that there were statistically significant differences between research groups in both year cohorts. Using this quality assurance procedure, the research project co-coordinator was able to identify areas of good practice and of concern, present the evidence to the respective research group leaders, ascertain the reasons for exceptional performances and to suggest remedial action where necessary.