Improving uncertainty in Widmark equation calculations:alcohol volume, strength and density

The Widmark equation is probably the most commonly used calculation for medicolegal purposes. Recently the National Research Council (USA) and the Forensic Science Regulator (UK) have called for the uncertainty of all results to be given with all forensic measurements and calculations. To improve the uncertainty of measurement of results from Widmark calculations we have concentrated on the uncertainties of measurement involved in the calculation of alcohol, that of the volume of alcohol, the concentration of alcohol and the density of alcohol as previous studies have investigated some of the other factors involved . Using experimental studies, the scientific literature and legal statutes, we have determined revised and improved uncertainties of the concentration of ethanol for Widmark calculations for both the USA and UK. Based on the calculations that we have performed we recommend the use of Monte Carlo Simulation for the determination of uncertainty of measurement for Widmark Calculations

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances in order to interpret and predict their effects upon humans. Experimental log D7.4, pKa and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3‐hydroxyphenazepam, 4’‐chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam) and compared with values generated by various software packages (ACD/I‐lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I‐LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future ‘training’ of predictive models for these new psychoactive substances

The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these ‘new’ benzodiazepines. In order to further understand the pharmacology of ‘new’ benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABAA receptors. The QSAR model returned an R2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future

Experimental evaluation of battery cells for space-based radar application

A test program was conducted to characterize five space-quality nickel-hydrogen (NiH2) battery cells. A subset of those tests was also done on five commercial nickel-cadmium (NiCd) cells, for correlation to the characteristics of an Energy Storage Unit Simulator. The test program implemented the recommendations of a 1991 study, as reported to IECEC-92. The findings of the tests are summarized, and expected impacts on the performance of the electrical power system (EPS) of a large space-based radar (SBR) surveillance satellite are derived. The main characteristics examined and compared were terminal voltage (average and transient) and capacity through discharge, equivalent series resistance, derived inductance and capacitance, charge return efficiency, and inter-pulse charge effectiveness

Impact of Artificially Induced Respiratory Deficient Yeast on Beer Flavor and Fermentation

<p>Respiratory deficient cells or “petites” are the most common type of mutation found in brewing yeast. High levels of petites are known to contribute to unwanted flavors in beer along with yeast flocculation problems during fermentation. However, a minimal amount is known regarding the impact of petites when present at naturally occurring frequencies. Accordingly, this study investigated if petites, which are present at low frequencies, affect beer flavor and fermentation profiles. Laboratory [20 mL] fermentations were undertaken with yeast that contained a range of petite populations 3.7, 5.1, 8.7, and 10.8%. During fermentation, the yeast in suspension, wort density, and alcohol were monitored. At the end of the fermentation, the beer was analyzed for volatile flavor compounds. Correlations between petite levels and levels of vicinal diketones, acetate esters, and medium chain fatty acid (MCFA) ethyl esters existed. Higher alcohol levels were unchanged (propan-1-ol, 3-methyl butanol, 2-methyl butanol, and isobutanol) with increasing levels of petite concentrations. Similarly, the yeast in suspension behavior and the change in wort density attenuation between the control and petite enriched fermentations were not significantly different (<i>P</i> > 0.05). This study suggests that low concentrations of petites in the pitched yeast would not be detectable in the final product characteristics.</p

PinR mediates the generation of reversible population diversity in Streptococcus zooepidemicus

Opportunistic pathogens must adapt to and survive in a wide range of complex ecosystems. Streptococcus zooepidemicus is an opportunistic pathogen of horses and many other animals, including humans. The assembly of different surface architecture phenotypes from one genotype is likely to be crucial to the successful exploitation of such an opportunistic lifestyle. Construction of a series of mutants revealed that a serine recombinase, PinR, inverts 114 bp of the promoter of SZO_08560, which is bordered by GTAGACTTTA and TAAAGTCTAC inverted repeats. Inversion acts as a switch, controlling the transcription of this sortase-processed protein, which may enhance the attachment of S. zooepidemicus to equine trachea. The genome of a recently sequenced strain of S. zooepidemicus, 2329 (Sz2329), was found to contain a disruptive internal inversion of 7 kb of the FimIV pilus locus, which is bordered by TAGAAA and TTTCTA inverted repeats. This strain lacks pinR and this inversion may have become irreversible following the loss of this recombinase. Active inversion of FimIV was detected in three strains of S. zooepidemicus, 1770 (Sz1770), B260863 (SzB260863) and H050840501 (SzH050840501), all of which encoded pinR. A deletion mutant of Sz1770 that lacked pinR was no longer capable of inverting its internal region of FimIV. The data highlight redundancy in the PinR sequence recognition motif around a short TAGA consensus and suggest that PinR can reversibly influence the wider surface architecture of S. zooepidemicus, providing this organism with a bet-hedging solution to survival in fluctuating environments

Thoracoscopy and talc poudrage compared with intercostal drainage and talc slurry infusion to manage malignant pleural effusion: the TAPPS RCT

Background: There are around 40,000 new cases of malignant pleural effusion in the UK each year. Insertion of talc slurry via a chest tube is the current standard treatment in the UK. However, some centres prefer local anaesthetic thoracoscopy and talc poudrage. There is no consensus as to which approach is most effective. Objective: This trial tested the hypothesis that thoracoscopy and talc poudrage increases the proportion of patients with successful pleurodesis at 3 months post procedure, compared with chest drain insertion and talc slurry. Design: This was a multicentre, open-label, randomised controlled trial with embedded economic evaluation. Follow-up took place at 1, 3 and 6 months. Setting: This trial was set in 17 NHS hospitals in the UK. Participants: A total of 330 adults with a confirmed diagnosis of malignant pleural effusion needing pleurodesis and fit to undergo thoracoscopy under local anaesthetic were included. Those adults needing a tissue diagnosis or with evidence of lung entrapment were excluded. Interventions: Allocation took place following minimisation with a random component, performed by a web-based, centralised computer system. Participants in the control arm were treated with a bedside chest drain insertion and 4 g of talc slurry. In the intervention arm, participants underwent local anaesthetic thoracoscopy with 4 g of talc poudrage. Main outcome measures: The primary outcome measure was pleurodesis failure at 90 days post randomisation. Secondary outcome measures included mortality and patient-reported symptoms. A cost–utility analysis was also performed. Results: A total of 166 and 164 patients were allocated to poudrage and slurry, respectively. Participants were well matched at baseline. For the primary outcome, no significant difference in pleurodesis failure was observed between the treatment groups at 90 days, with rates of 36 out of 161 (22%) and 38 out of 159 (24%) noted in the poudrage and slurry groups, respectively (odds ratio 0.91, 95% confidence interval 0.54 to 1.55; p = 0.74). No differences (or trends towards difference) were noted in adverse events or any of the secondary outcomes at any time point, including pleurodesis failure at 180 days [poudrage 46/161 (29%), slurry 44/159 (28%), odds ratio 1.05, 95% confidence interval 0.63 to 1.73; p = 0.86], mean number of nights in hospital over 90 days [poudrage 12 nights (standard deviation 13 nights), slurry 11 nights (standard deviation 10 nights); p = 0.35] and all-cause mortality at 180 days [poudrage 66/166 (40%), slurry 68/164 (42%); p = 0.70]. At £20,000 per quality-adjusted life-year gained, poudrage would have a 0.36 probability of being cost-effective compared with slurry. Limitations: Entry criteria specified that patients must be sufficiently fit to undergo thoracoscopy, which may make the results less applicable to those patients presenting with a greater degree of frailty. Furthermore, the trial was conducted on an open-label basis, which may have influenced the results of patient-reported measures. Conclusions: The TAPPS (evaluating the efficacy of Thoracoscopy And talc Poudrage versus Pleurodesis using talc Slurry) trial has robustly demonstrated that there is no additional clinical effectiveness or cost-effectiveness benefit in performing talc poudrage at thoracoscopy over bedside chest drain and talc slurry for the management of malignant pleural effusion. Trial registration: Current Controlled Trials ISRCTN47845793. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 26. See the NIHR Journals Library website for further project information

Post-mortem diagnosis of kidney impairment:an experimental study

The determination of the role that drugs may have played in a death is an important part of the investigation into unexplained deaths. Renal impairment may lead to a reduction in drug excretion rate and therefore an accumulation of drugs or metabolites, leading to possible toxic or lethal effects. Creatinine levels are known to be stable in the post mortem period and in life can give an indication of kidney function. There are however widely reported limitations when using creatinine in isolation and so we investigated the usefulness of using estimated glomerular filtration rate (eGFR) for scoring an individual as having renal impairment using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. We analysed unpreserved vitreous for creatinine in 812 individuals using an isotope dilution mass spectrometry (ID-MS) traceable enzymatic. We found that the biochemical analysis of post mortem vitreous creatinine and subsequent calculation of eGFR is a useful adjunct to the standard testing that takes place during a post-mortem examination and can assist in death investigation. Using an eGFR of &lt;60 mL/min/1.73 m2 gave a sensitivity of 94.3% and specificity of 97.3% when scoring an individual as having renal impairment. We therefore recommend the calculation of eGFR for the determination of possible renal impairment in post mortem investigations. It is, of course, always pertinent to interpret any results using a wealth of case information. Extreme caution should be exercised in cases where insufficient clinical information/history is available, particularly in cases in which there is suspected diabetic ketoacidosis, dehydration or hospitalisation prior to death

Recovery of cobalt from lithium-ion batteries using fluidised cathode molten salt electrolysis

The future need to recycle enormous quantities of Li-ion batteries is a consequence of the rapid rise in electric vehicles required to decarbonise the transport sector. Cobalt is a critical element in many Li-ion battery cathode chemistries. Herein, an electrochemical reduction and recovery process of Co from LiCoO2 is demonstrated that uses a molten salt fluidised cathode technique. For the Li-Co-O-Cl system, specific to the experimental process, a predominance diagram was developed to aid in understanding the reduction pathway. The voltammograms indicate two 2-electron transfer reactions and the reduction of CoO to Co at -2.4 V vs. Ag/Ag+. Chronoamperometry revealed a Faradaic current efficiency estimated between 70-80% for the commercially-obtained LiCoO2 and upwards of 80% for the spent Li-ion battery. The molten salt electrochemical process route for the recycling of spent Li-ion batteries could prove to be a simple, green and high-throughput route for the efficient recovery of critical materials

Within-host spatiotemporal dynamics of systemic Salmonella infection during and after antimicrobial treatment

$\textbf{Objectives:}$ We determined the interactions between efficacy of antibiotic treatment, pathogen growth rates and between-organ spread during systemic $\textit{Salmonella}$ infections. $\textbf{Methods:}$ We infected mice with isogenic molecularly tagged subpopulations of either a fast-growing WT or a slow-growing $\Delta$$\textit{aroC Salmonella}$ strain. We monitored viable bacterial numbers and fluctuations in the proportions of each bacterial subpopulation in spleen, liver, blood and mesenteric lymph nodes (MLNs) before, during and after the cessation of treatment with ampicillin and ciprofloxacin. $\textbf{Results:}$ Both antimicrobials induced a reduction in viable bacterial numbers in the spleen, liver and blood. This reduction was biphasic in infections with fast-growing bacteria, with a rapid initial reduction followed by a phase of lower effect. Conversely, a slow and gradual reduction of the bacterial load was seen in infections with the slow-growing strain, indicating a positive correlation between bacterial net growth rates and the efficacy of ampicillin and ciprofloxacin. The viable numbers of either bacterial strain remained constant in MLNs throughout the treatment with a relapse of the infection with WT bacteria occurring after cessation of the treatment. The frequency of each tagged bacterial subpopulation was similar in the spleen and liver, but different from that of the MLNs before, during and after treatment. $\textbf{Conclusions:}$ In $\textit{Salmonella}$ infections, bacterial growth rates correlate with treatment efficacy. MLNs are a site with a bacterial population structure different to those of the spleen and liver and where the total viable bacterial load remains largely unaffected by antimicrobials, but can resume growth after cessation of treatment.This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) grant number BB/M000982/1 (http://www.bbsrc.ac.uk/research/grants/grants/AwardDetails.aspx?FundingReference=BB/M000982/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript